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Building a Future Free of Age-Related Disease

The Need for Better Aging Biomarkers

As human life expectancy has increased throughout the 20th and 21st centuries, this has led to a steady increase in the population of older people. With that increase has come the rise of age-related diseases and disabilities.

As a result, it is becoming ever more important to develop preventative strategies to monitor and maintain health as well as therapies that directly address the various aging processes to delay or prevent the onset of age-related diseases.

One of the ways we can do this is by developing more effective ways to measure how someone is aging; this means developing high-quality aging biomarkers. The challenge in creating such biomarkers has always been the fundamental question of what we measure.

Chronological age is a poor indication of how someone might be aging and is not a good way to ascertain an individual’s risk factor for various age-related diseases. This is simply because everyone ages differently and at different rates. While everyone ages due to the same processes, the speed at which these different processes occur can vary between individuals.

While individual biomarkers are good for measuring a certain aspect of aging in a very focused way, and they are indeed useful in this capacity, they do not give an overall picture of how someone is aging and where to focus preventative efforts [1].

The literature is replete with examples of biomarkers that measure physical function, anabolic response, inflammation levels, and immune system aging [2-10].

Biomarkers have their limitations

Taken individually, these are useful, but many biomarkers have their limitations. Biomarkers such as β-galactosidase, which is very popular among researchers investigating cellular senescence, has some limits, especially if used as the only or one of few biomarkers during an experiment [11].

Another popular biomarker of aging is the measurement of telomeres. However, this also has some limitations, depending on the particular method used [12-13]. Indeed, some studies have investigated its validity as an aging biomarker and argue that, while useful, it is not really an aging biomarker in the strict sense [14].

A system analysis approach to aging biomarkers

In order to get the bigger picture, we need to move beyond simple approaches to a systems analysis approach that examines multiple biomarkers at once [15].

A number of approaches to this issue have been proposed and even tested. Arguably, one of the most well-known methods for ascertaining biological age is the DNA methylation clock developed by Horvath; it can, in many ways, be considered the gold standard for aging biomarkers[16].

Other approaches that consider multiple biomarkers have also been proposed; such systems evaluate a number of biomarkers to give a ‘score’ as an overall indication of aging rate [17-20]. More recently, a package of 19 biomarkers has been suggested as another approach to evaluating age [21].

There are numerous similar proposals in literature to evaluate aging with a wider set of biomarkers, and curious people do not have to search far to find them.

There is an urgent need to not only develop more accurate biomarkers but also to package them into a systems analysis approach. This would allow researchers developing drugs and therapies that target the aging processes to ascertain efficacy to a much greater degree. It could also allow better monitoring of an individual’s health  and allow physicians to identify and address areas of concern to a far greater degree of accuracy.

Conclusion

The development of better biomarkers and systems capable of packaging them into compact solutions is very important to aging research. The rising popularity of health wearables and other personal health monitoring equipment also has the potential to allow the average person to take more control over his or her health. Such approaches could be combined with other functional aging tests, such as the H-Scan or the updated version being developed as part of a fundraising project at Lifespan.io. The development of biomarkers and systems that deliver them efficiently and at an affordable cost should, therefore, be a high priority.

Literature

[1] Karasik, D., Demissie, S., Cupples, L. A., & Kiel, D. P. (2005). Disentangling the genetic determinants of human aging: biological age as an alternative to the use of survival measures. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 60(5), 574-587.

[2] Gruenewald, T. L., Seeman, T. E., Ryff, C. D., Karlamangla, A. S., & Singer, B. H. (2006). Combinations of biomarkers predictive of later life mortality. Proceedings of the National Academy of Sciences, 103(38), 14158-14163.

[3] Walston, J., Hadley, E. C., Ferrucci, L., Guralnik, J. M., Newman, A. B., Studenski, S. A., … & Fried, L. P. (2006). Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. Journal of the American Geriatrics Society, 54(6), 991-1001.

[4] Stenholm, S., Maggio, M., Lauretani, F., Bandinelli, S., Ceda, G. P., Di Iorio, A., … & Ferrucci, L. (2010). Anabolic and catabolic biomarkers as predictors of muscle strength decline: the InCHIANTI study. Rejuvenation research, 13(1), 3-11.

[5] Banerjee, C., Ulloor, J., Dillon, E. L., Dahodwala, Q., Franklin, B., Storer, T., … & Montano, M. (2011). Identification of serum biomarkers for aging and anabolic response. Immunity & Ageing, 8(1), 5.

[6] Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69(Suppl 1), S4-S9.

[7] Bürkle, A., Moreno-Villanueva, M., Bernhard, J., Blasco, M., Zondag, G., Hoeijmakers, J. H., … & Gonos, E. S. (2015). MARK-AGE biomarkers of ageing. Mechanisms of ageing and development, 151, 2-12.

[8] Cohen, A. A., Milot, E., Li, Q., Bergeron, P., Poirier, R., Dusseault-Belanger, F., … & Fried, L. P. (2015). Detection of a novel, integrative aging process suggests complex physiological integration. PLoS One, 10(3), e0116489.

[9] Catera, M., Borelli, V., Malagolini, N., Chiricolo, M., Venturi, G., Reis, C. A., … & Ostan, R. (2016). Identification of novel plasma glycosylation-associated markers of aging. Oncotarget, 7(7), 7455.

[10] Peterson, M. J., Thompson, D. K., Pieper, C. F., Morey, M. C., Kraus, V. B., Kraus, W. E., … & Cohen, H. J. (2015). A novel analytic technique to measure associations between circulating biomarkers and physical performance across the adult life span. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glv007.

[11] Yang, N. C., & Hu, M. L. (2005). The limitations and validities of senescence associated-β-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Experimental gerontology, 40(10), 813-819.

[12] Montpetit, A. J., Alhareeri, A. A., Montpetit, M., Starkweather, A. R., Elmore, L. W., Filler, K., … & Collins, J. B. (2014). Telomere length: a review of methods for measurement. Nursing research, 63(4), 289.

[13] Bernadotte, A., Mikhelson, V. M., & Spivak, I. M. (2016). Markers of cellular senescence. Telomere shortening as a marker of cellular senescence. Aging (Albany NY), 8(1), 3.

[14] Der, G., Batty, G. D., Benzeval, M., Deary, I. J., Green, M. J., McGlynn, L., … & Shiels, P. G. (2012). Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland?. PLoS One, 7(9), e45166.

[15] Zierer, J., Menni, C., Kastenmüller, G., & Spector, T. D. (2015). Integration of ‘omics’ data in aging research: from biomarkers to systems biology. Aging cell, 14(6), 933-944.

[16] Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome biology, 14(10), 3156.

[17] Levine, M. E. (2013). Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age?. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 68(6), 667-674.

[18] Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., … & Sugden, K. (2015). Quantification of biological aging in young adults. Proceedings of the National Academy of Sciences, 112(30), E4104-E4110.

[19] Peterson, M. J., Thompson, D. K., Pieper, C. F., Morey, M. C., Kraus, V. B., Kraus, W. E., … & Cohen, H. J. (2015). A novel analytic technique to measure associations between circulating biomarkers and physical performance across the adult life span. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glv007.

[20] Lara, J., Cooper, R., Nissan, J., Ginty, A. T., Khaw, K. T., Deary, I. J., … & Mathers, J. C. (2015). A proposed panel of biomarkers of healthy ageing. BMC medicine, 13(1), 222.

[21] Sebastiani, P., Thyagarajan, B., Sun, F., Schupf, N., Newman, A. B., Montano, M., & Perls, T. T. (2017). Biomarker signatures of aging. Aging Cell.

Treating Diseases with a Protein Missile System

Researchers at the University of Dundee have shown that it is possible to target and destroy specific proteins within cells using a new directed protein missile system. This is very interesting, as it raises the possibility of targeting aberrant proteins present in diseases that currently have no drug that affects them.

This opens the door to treating a range of diseases, as well as potentially being useful in directly targeting proteins involved in the aging process. Before we take a look at the research, let’s recap on why proteins are important, what they do, and how they relate to aging and diseases.

So what are proteins?

Proteins are often called the building blocks of life, and they are critical to the operation of our cells and therefore to our lives. Proteins are produced by the cell and perform a huge variety of functions, such as activating the immune response against pathogens, and regulating metabolism and cellular functions. They do the majority of the work in cells and are required for maintaining the structure, function, and regulation of the body’s tissues and organs.

Proteins are made up of hundreds or even thousands of smaller units called amino acids, which are linked together in long chains. There are twenty different amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique structure and its function. Proteins can be categorized according to their function within the body.

Function

Description

Antibody

Antibodies bind to specific foreign particles, such as viruses and bacteria, as part of the immune response and to help protect the body.

Enzyme

Enzymes perform almost all of the thousands of chemical reactions that take place within cells. They also assist with the formation of new molecules by interpreting the genetic information stored in DNA.

Messenger

Messenger proteins, such as some hormones, transmit signals to coordinate biological processes between the different cells, tissues, and organs.

Structural component

These proteins provide structure and support for cells. In a larger context, they also allow the body to move.

Transport/storage

These proteins bind and carry atoms and small molecules within cells and through the body.

Undruggable proteins

In the majority of diseases, the protein function is altered due to genetic mutation (damage to our DNA) or a deregulated environment where there are too many proteins or too few produced. This change in the function of proteins then causes havoc in the cell and leads to diseases and drives the aging processes too.

During aging, proteins can become misfolded, which leads to protein aggregation and the onset of diseases like Alzheimer’s and Parkinson’s, where damaged proteins build up and destroy brain cells. If these damaged proteins could be targeted effectively, it could potentially be a way to treat neurodegenerative diseases.

Some researchers suggest that only a small number of proteins can actually be targeted by conventional drugs, and the majority of proteins remain untouchable or undruggable. So, being able to target and degrade the proteins in the cell has a vast scope for treating many diseases both age-related and otherwise.

Introducing AdPROM

A research team at Dundee University, led by Dr. Gopal Sapkota has created an Affinity-directed PROtein Missile (AdPROM) system that allows for the precise and rapid targeting and destruction of proteins in the cell. The paper published recently here follows on from earlier work by the same team [1-2].

AdPROM uses small affinity probes, termed nanobodies or monobodies, which bind and recruit target proteins to the cellular protein degradation system to be destroyed.  

In a university press release, Dr. Sapkota commented “For the first time we have shown that it is possible to target endogenous proteins for complete degradation with AdPROM,” and “This is extremely exciting and has far-reaching applications and implications for both research and drug discovery. Being able to selectively degrade target proteins in cells rapidly is desirable in research and therapeutics.”

The targeting and rapid destruction of specific proteins could potentially allow scientists to determine the effect of removing these proteins and the possible reversal of disease state by doing so.

The removal of excessive malfunctioning proteins from cells and tissues using AdPROM could be a huge step for medicine but there is much work to be done. Before this technology can be deployed in humans, it would need to pass through the clinical trial process so until then there is much more work ahead for the researchers here. Dr. Sapkota believes that scientific developments in gene delivery techniques could be the way to use AdPROM in the future.

“The AdPROM technology is quite simple to assemble and versatile for use in any cell,” said Dr. Sapkota. “Basically, it requires an affinity probe that selectively recognises the endogenous target protein of choice. With rapid advances in technologies, it won’t be too long before we have access to affinity probes against pretty much every target protein.”

This is true, as technology is advancing rapidly and gene therapy delivery systems are becoming more sophisticated and refined with each passing year.

“This is technology that we can hopefully use to expedite and prioritise drug discovery. Getting a single molecule developed against a target protein costs a lot of money and resources so it is impossible to do this for every protein. AdPROM allows us to manipulate proteins, study their individual functions and find out what happens when they are destroyed. It will allow us to refine the list of targets very, very quickly. Indeed, we are already collaborating with major pharmaceutical companies to streamline drug targets with AdPROM,” Dr. Sapkota concludes.

Conclusion

Should clinical trials pan out, the AdPROM system could be a potent weapon in the fight against all kinds of diseases, including age-related diseases like Alzheimer’s, Parkinson’s, heart disease, and cancer. We wish Dr. Sapkota and his team the best of luck, and we will be watching progress with great interest.

Literature

[1] Fulcher, L. J., Hutchinson, L. D., Macartney, T. J., Turnbull, C., & Sapkota, G. P. (2017). Targeting endogenous proteins for degradation through the affinity-directed protein missile system. Open Biology, 7(5), 170066.

[2] Fulcher, L. J., Macartney, T., Bozatzi, P., Hornberger, A., Rojas-Fernandez, A., & Sapkota, G. P. (2016). An affinity-directed protein missile system for targeted proteolysis. Open Biology, 6(10), 160255.

 

How Population Aging First Became an International Concern

Today, we bring you an interview with Dr. Marvin Formosa, director of the International Institute on Ageing of the United Nations, Malta (INIA). First, let’s find out how the issue of population aging was first introduced into the agenda of the United Nations and why the UN body focused on aging is located in Malta.

Malta was the first to recognise aging as an international problem

There are plenty of philosophers who have tried to understand aging on both the individual and social levels, and there are many scientists who have been increasingly improving our knowledge of aging as a set of biological processes. There have also been certain moments in time when humanity has made crucial steps towards a better future for everyone. One of these steps was the recognition that aging is a matter of international concern.

The matter was successfully brought to the attention of the United Nations by the government of Malta in 1968. This led to a number of regional conferences aimed at analyzing the situation and preparing a report on population changes in different parts of the world.

After nearly a decade, the nature of the received data resulted in the decision to hold the very first World Assembly on Aging, which took place in Vienna, Austria in 1982. This assembly brought together more than 1,000 participants from 124 member states. International bodies and non-governmental organisations have sent their representatives to help elaborate the first-ever International Plan of Action on Aging (also known as the Vienna Plan on Aging).

This first strategic document made clear the economic and social consequences of population aging and provided guidance to the member states on how to adapt to the growing needs of older people. The need for a coordination and education center on the problems of aging also became evident; this is why the UN Economic and Social Council recommended that the UN leaders they establish the International Institute on Aging.

Malta becomes the UN International Institute on Ageing

Due to the role that Malta has played in promoting this important matter, in October of 1987, the United Nations signed an official agreement with the government of Malta in order to found a new specialized body under the auspices of the United Nations.

The International Institute on Ageing (INIA) was inaugurated on April 15th, 1988 by Javier Perez de Cuellar, who served as the Secretary-General of the United Nations during that period. The main activities of the Institute include multi-disciplinary education and training in specific areas related to aging along with data collection, information exchange, technical co-operation, and research and publications.

Close international cooperation allows the Institute to organize multiple “in situ” education programs to analyse local socio-economic conditions and needs of the elderly in developed and developing countries, facilitate knowledge dissemination, and hence foster the development of evidence-based policy and action plans on aging.

To date, more than 3000 specialists from all over the world have participated in these international education programs, such as the School on Gerontology and Geriatrics. The changes related to population aging that our society is going through require all stakeholders to have a systemic vision on the issue in order to make wise decisions.

This is why we at LEAF/Lifespan.io decided that I should attend the closest “in situ” INIA training program, which was held in Saint-Petersburg, Russia on April 10-15, and share my knowledge and impressions with the team and the community.

I took the opportunity during the conference to interview Dr. Marvin Formosa, the director of the International Institute on Ageing, United Nations – Malta (INIA).

We would like to thank Dr. Formosa for taking the time to speak with us at the event, and we appreciate his insights.

Error CORRECTion for CRISPR

The CRISPR system (Clustered Regularly Interspaced Short Palindromic Repeats) has exploded onto the biotech sector as a relatively simple, highly efficient, and fast method for precisely introducing breaks into genomic loci [1-2]. The realization that it is a prokaryotic acquired immune system, although less often mentioned, has been equally paradigm changing [3]. Ironically, it’s the system’s high efficiency that poses a problem when editing mammalian genomes, a problem that Paquet et al. ingeniously solve in this new study.

In very brief summary, two components are required for the CRISPR system to function: a protein endonuclease, termed Cas9 in the original system, and a short “guide” RNA (gRNA) that guides the endonuclease to a complementary genomic site corresponding to the 5′-terminal 20 bases of the gRNA. These are usually expressed from one plasmid.

A second necessity for the system to function is the presence of a short sequence present in the genomic target site that is adjacent to the gRNA target site. This is termed the Protospacer Adjacent Motif (PAM) and varies between different versions of Cas proteins, with NGG being recognized by the original system adapted from the bacterium S. pyogenes.

Since then, the CRISPR system toolkit has been expanded to not only to nick and induce double-stranded breaks in DNA but also cleave RNA, activate and repress genes, fluorescently label genomic loci, recognize different PAM sites, and introduce epigenetic modifications [4-8]. Its original use, however, has been to create a precise double-stranded break at genomic loci for the purpose of accurately modifying genomes.

This second modification step requires the presence of a homology mediated repair (HMR) DNA template, which the cell’s endogenous repair enzymes use to copy in the modified sequence. This is the troublesome step in which low efficiency still plagues researchers who wish to genetically modify loci accurately in mammalian cells. Because the CRISPR system is so efficient, it can re-bind to the endogenous PAM site and re-cut the locus.

A problem with accuracy

In mammalian cells, the error prone NHEJ (Non Homologous End Joining) repair pathway is dominant, leading to insertion/deletion mutations in the majority of targeted cells. Thus, only a small percentage of CRISPR-altered mammalian cells actually have the precise modification that you want. This also makes it difficult to generate heterozygote cell lines, as the majority of the time, both alleles on both chromosomes will be targeted and altered.

To solve this problem, Paquet et al. have developed and expanded a technique initially shown to work in prokaryotes to now avoid such re-cutting in mammalian cells in an Alzheimer’s model system [9].

In what is possibly one of the most contorted recursive acronyms ever devised, their ingenious system, termed CORRECT (COnsecutive Re-guide or Re-Cas steps to Erase CRISPR/Cas-blocked Targets), works by introducing “blocking” mutations into either the PAM site or the guide RNA binding site on the HMR template. Doing so means that, after the CRISPR system has recognized either the native PAM or guide RNA binding site in the genomic locus, the introduced modification will also contain new mutant PAM and/or guide RNA binding sites that are not recognized.

This greatly enhances the frequency of correct mutants from about 20% in HMR targeted cells to about 80%. Furthermore, the mutant PAM and guide RNA binding sites can then be reverted back to normal using a second round of CRISPR, generating a truly scar-less site. Not content there, the authors also present two additional techniques that can readily generate heterozygote mutant cell lines as well. This year, Kwart et al. have published the detailed protocols for these methods [10]. At least one additional problem needs to be solved to make CRISPR work optimally in mammalian cells.

This is centered on the very low efficiency of HDR vs. NHEJ, with the latter being favored. Although the authors demonstrated that the efficiency of obtaining correct HMR modified cells rose to 80-90%, one must realize that this percentage is only out of those cells that initially used HMR. That total is only 1-10% of all modified cells; the majority of 90-99% used error-prone NHEJ.

Conclusion

Once this hurdle is finally overcome, and many groups are actively working on solving this problem, the CRISPR system for genome modification may very well become as close to perfect as is physically possible.

Literature

1. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. Science. 2012 Aug 17;337(6096):816-21. 2. Multiplex genome engineering using CRISPR/Cas systems. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Science. 2013 Feb 15;339(6121):819-23. doi: 3. Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. Mojica FJ, Díez-Villaseñor C, García-Martínez J, Soria E. J Mol Evol. 2005 Feb;60(2):174-82. 4. Imaging genomic elements in living cells using CRISPR/Cas9. Chen B, Huang B. Methods Enzymol. 2014;546:337-54. 5. Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Bikard D, Jiang W, Samai P, Hochschild A, Zhang F, Marraffini LA. Nucleic Acids Res. 2013 Aug;41(15):7429-37. 6. Programmable RNA recognition and cleavage by CRISPR/Cas9. O’Connell MR, Oakes BL, Sternberg SH, East-Seletsky A, Kaplan M, Doudna JA. Nature. 2014 Dec 11;516(7530):263-6 7. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Hilton IB, D’Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, Gersbach CA. Nat Biotechnol. 2015 May;33(5):510-7. 8. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y, Zhang F. Cell. 2013 Sep 12;154(6):1380-9. Erratum in: Cell. 2013 Oct 10;155(2):479-80. 9. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Paquet D, Kwart D, Chen A, Sproul A, Jacob S, Teo S, Olsen KM, Gregg A, Noggle S, Tessier-Lavigne M. Nature. 2016 May 5;533(7601):125-9. 10. Precise and efficient scarless genome editing in stem cells using CORRECT. Kwart D, Paquet D, Teo S, Tessier-Lavigne M. Nat Protoc. 2017 Feb;12(2):329-354.
Computer brain

Dr. Alex Zhavoronkov – A.I. Versus Aging

The battle against aging is not going to be an easy one, and it will likely require the most refined tools modern science has to offer. Among them, artificial intelligence may be one of the most promising and is being extensively used by biogerontology researchers such as Dr. Alex Zhavoronkov.

Helping to drive progress in rejuvenation biotechnology

Boasting an impressive collection of degrees—among which a Ph.D. in biophysics, an MSc in biotechnology, and a BA in Computer science—Dr. Zhavoronkov has had an equally impressive career in the fields of biogerontology and regenerative medicine. He is the director of IARP—the International Aging Research Portfolio—and of the UK-based charity Biogerontology Research Foundation.

For several years now, he has been head of the Regenerative Medicine Laboratory at the Centre for Pediatric Hematology, Oncology and Immunology and adjunct professor at the Institute of Physics and Technology in Moscow.

Since 2014, he’s also the CEO of Insilico Medicine, a bioinformatics company which he co-founded. The company, which was awarded the ‘Most Promising Company’ title at the Palo Alto Personalised Medicine World Conference in 2015, focuses on extending healthy longevity using A.I. to discover new drugs and develop biomarkers for aging.

One of its most notable projects is OncoFinder, an algorithm used to analyze the activity of molecular pathways involved in both normal and pathological conditions, from growth and development to aging and cancer. The algorithm can be used to predict which drugs could prove the most effective in the treatment of cancer, for example, or to determine which pathways are involved in age-related diseases.

Dr. Zhavoronkov is a longevity enthusiast and he believes we can push the longevity record past the current 122 years.

Poised for a revolution in rejuvenation research

He compares the current state of radical life-extension research to that of computer science in the late 70s, when all the building blocks of the upcoming revolution were either in place already or about to be. To maximise his odds to see the dawn of rejuvenation biotechnology, Alex maintains a strict, healthy regimen that includes regular exercising, monitoring his health conditions and a variety of drugs and supplements tailored to his specific situation.

His current ambitious yet achievable goal is to reach 150 years of age, and he certainly does not think it would be boring to live for that long. He argues life should never be boring and that the way to go to avoid it is finding research interests and passions to motivate oneself.

In fact, he further argues, the major challenge to overcome to defeat aging is represented by psychological aging—the tendency people have to accept the decline that comes with age and the changes in behavior and attitudes that this imposes on them.

This aspect is one of the topics he discussed in his book The Ageless Generation: How Advances in Biomedicine Will Transform The Global Economy. Together with an ever-growing number of specialists of the field, Dr. Zhavoronkov endorses the idea that aging is nothing but a complex, multifactorial disease, and that it should be officially classified as such.

Whilst we haven’t brought the aging processes under medical control yet, Alex thinks it is possible, and that eliminating the pain and suffering that currently characterizes late life is a worthy and achievable goal. Already today, he argues, people who are reasonably healthy in their 70s stand a fighting chance of living past 150.

We took the opportunity to catch up with Alex and ask him a few questions about his work and the field of aging research.

Hi, Alex, could you begin by explaining what first attracted you to science and in particular the study of aging and why you believe aging is a problem to be solved?

Since very early childhood I asked myself one question: “Why in Star Wars, Star Trek and other Sci Fi movies and books people invent space travel, medical droids and other marvelous technologies, but still grow old, age and die?”. In order to go into space for the extended periods of time, one would need to live longer and be resistant to all kinds of stress including radiation. Plus, I had a crush on Madonna and really did not want her to age and there are many other reasons.

One reason above all is that there is no point in living if you can’t keep continuously improving no matter how hard you try. People, who accumulate wealth do not really own anything, they rent assets for as long as they live. But before going all-in into biomedicine, I went into computer science, did my first bachelor degrees at Queen’s University in Canada and made some money to ensure that I can sustain for a few years and support my own research.

I went into high-performance computing and managed to get into the high-level position at a graphics processing unit (GPU) company called ATI Technologies at a reasonably young age fifteen years ago. When I reached a reasonably comfortable financial situation, I decided to quit and went to do my graduate work in biosciences looking for ways to extend healthy productive longevity. I worked in a number of areas related to aging research and along the way, I got my masters and Ph.D. degrees, got two laboratories and worked for a number of biotechnology companies.

In 2010, after a decade of education and research, I realized that aging is a very complex multifactorial process and that humans are very different from model organisms. And we need to focus on developing the core technology that can be used to build a sustainable business around aging research so that it can unfold and demultiplex into many directions to prevent the transformation of aging into a disease.

Since January 2014 I have been running Insilico Medicine, which takes an umbrella view on the field with over 170 research projects and over 150 collaborators worldwide. I have no doubt that aging is a problem that can be solved within our lifetimes unless we see a major economic crisis, a global war, or both.

Your work focuses on computational medicine, how would you explain this relatively new field of science to our readers?

Computational biomedicine is a very broad field of research, where computational methods and tools are applied for diagnosis, treatment, and research. The field has been around since the invention of electronic analytical equipment, but in recent years it got a major boost due to the availability of Big Data, increases in computing power, breakthroughs in machine learning and convergence of the many fields of science and technology.

You are the CEO of Insilico Medicine. What are the main goals of the company for the next 5 years? Can we expect breakthroughs in personalized medicine?

Our long-term goal is to continuously improve human performance and prevent and cure the age-related diseases. In 5 years we want to build a comprehensive system to model and monitor the human health status and rapidly correct any deviations from the ideal healthy state with lifestyle or therapeutic interventions. Considering what we already have, I hope that we will be able to do it sooner than in 5 years.

One reason why we can manage over 170 projects is that we use agile development practices and approach every project as a software development project. We treat aging as a salami, constantly “cutting” thin slices and I think we are halfway through. In 5 years you can definitely expect breakthroughs in personalized medicine and we are not the only company working in the field, so there will be many breakthroughs on the many fronts.

The main breakthroughs I can promise from Insilico are in the area of multimodal biomarkers of aging, where we take as much data available for an individual from simple pictures and regular blood tests to very expensive molecular and imaging data and turn it into a model, which can be used to make a broad range of predictions, recommendations, and treatments. We are entering the era of personalized drug discovery and regenerative medicine.

One of our major contributions to the field was the application of deep neural networks for predicting the age of the person. People are very different and have different diseases. But if you want to find just one feature, which is biologically relevant and can be predicted using many data types – it is the person’s date of birth.

So we build all kinds of predictors of chronological age and then look at what features and at what levels are most important and can be used to infer causality and be targeted with interventions. I think that this approach is novel and will result in many breakthroughs. Here are the two slides that illustrate this idea:

Another set of breakthroughs is likely to come from our work in the generative adversarial networks (GANs) and reinforcement learning (RL), where we are experimenting with the design of new molecules with the desired properties and reconstruct the incomplete data sets with missing values. Here is a public version of our current drug discovery pipeline:

We published some of the proofs of concept for at least some of these steps so that other people could go this route and to save time when explaining this approach to our partners in Big Pharma.

How do you decide what projects to get involved in?

The way we prioritize projects at Insilico Medicine is by looking at the number of QALY each project can generate. Most pharmaceutical companies, governments, and philanthropists do not realize that aging research generates the maximum number of QALY per dollar spent. It is the most altruistic cause and the most effective investment.

If you add just one year of life to everyone on the planet, you generate over 7 billion QALY. The average reasonable cost per QALY is around $50,000. So it is possible to generate several hundred trillion dollars by extending the life of everyone on the planet with a simple intervention.

Will you tell us a little bit about your team at Insilico? Is it easy to get on board or do you have some sort of test?

Over the past two years, we hire through hackathons and mini-competitions that we either organize or support. Several of our core deep learning specialists and bioinformaticians were hired in this manner. We also work with the young bright scientists, who come to us looking for a project.

We usually give them a difficult or impossible task and if they come up with a solution, we integrate them into the team. We usually want to ensure that the person is not driven by the monetary aspect of employment and will stay with us for over a year. And sometimes we allow and even encourage the person to remain part-time in academia.

Today we have R&D resources in Baltimore, Brussels, Moscow, St. Petersburg, Oxford, and Seul. This year we will try to grow Insilico Korea, conduct one or two SkinHack hackathons using our AgeNet.Net system and establish closer collaboration with the partners in Korea. We also like hiring people in Russia. The level of programming talent is very high, people are loyal, curious, dedicated and mission-driven.

And if you have any negative feelings with regards to Russia, remember that there are several countries considered to be friendly that are actually kingdoms. So you need companies like ours with strong humanitarian values to create new industries and reduce the country’s dependence on oil.

We have heard you make your team members pass a course on bioinformatics to join the Longevity Pride club, can you tell us a bit more about that?

All team members join voluntarily and usually through hackathons or collaborations. Longevity Pride is more than a club or a fraternity. It is a philosophy centered around the idea that we can model the human biological processes so well that at some point in time we could develop personalized interventions that are safe and effective.

We are a community of like-minded individuals with strong background in IT or bioinformatics, who embrace the computational approach for extending healthy human longevity. We have a code of conduct, a specially-designed ring. It is not a secret society. But if you see someone with a ring of this design, the person is likely to be very good in bioinformatics and is contributing to aging research.

How would you advise someone interested in working in computational medicine to get involved?

I recommend going to a few conferences on aging and AI. This year I co-organized two innovation forums during the EMBO/Basel Life conference (www.BaselLife.org): 4th Annual Aging Research for Drug Discovery Forum and 1st Artificial Intelligence and BlockChain Technology in Healthcare Forum 11-13 of September 2017.

If you want to get a very long introduction to aging research in the context of effective altruism, a few ideas on how to get involved, Insilico and economics of aging and longevity, here are the slides from a 2-hour presentation I recently gave to a group of IT students:

You have already used your approach for cancer with the OncoFinder study[1-2]. This seems like a radical new way of conducting research, how successful has this method been so far?

The OncoFinder demonstrated excellent results in helping personalized existing treatments for individual patients and improve clinical trials enrollment practices. But for drug discovery, we developed tools like the iPANDA algorithm and its derivatives to track the minute changes between the various signaling states in multiple tissues and identified the molecules that can target these changes. Some of these molecules have been licensed to professional drug developers and some are being validated by the contract research organizations (CROs) for Insilico Medicine.

Can we apply the lessons learned from OncoFinder to the various aging processes to treat age-related diseases for example? After all cancer and aging are closely connected right?

Yes, that was the original idea. We developed a set of highly sensitive differential pathway perturbation analysis algorithms like the OncoFinder and the iPANDA to understand the minute changes between the young healthy state, old state and diseases like cancer. The iPANDA is an excellent tool for the biologically-relevant dimensionality reduction for the training of the deep neural networks.

Aging and cancer are very closely related and cancer is the age-related disease. However, one of the reasons we study cancer is because tissue-specific cancer is a very good model for validating our biomarkers and drug scoring algorithms. Many other diseases are systemic and affect multiple tissues and it is very difficult to perform validation on human tissue.

AI is a very hot topic right now and its potential use in medicine, and of course you are heavily involved in that yourself [3]. Do you think AI could help us to bring aging under comprehensive medical control?

I think that applying AI to aging is the only way to bring it under the comprehensive medical control. Our AI ecosystem is comprised of multiple pipelines. With our drug discovery and biomarker development pipelines we can go after almost every disease and we even have several projects in ALS.

While our proof of concept studies are usually done in cancer, because it is easier to validate the predictions, we go after many disease areas. And since we are considering aging as a form of disease, many of the same algorithms are used to develop biomarkers and drugs to prevent and possibly even restore the age-associated damage.

Our technology also adds credibility to aging research for the pharmaceutical R&D. For example, some of the most significant breakthroughs in modern medicine were made in immuno oncology, where the patient’s’ immune system is used to attack the tumor. Many pharmaceutical companies that run clinical trials cut off enrollment into the clinical trials by age, so older patients will not be eligible.

We have many tools to evaluate the immune fitness of the patient and tools to boost the response rate to the immuno oncology drugs. Understanding aging in this context is extremely important, otherwise many patients will be left behind. According to recent studies, it may take up to 17 years to bring a new treatment from a lab to market, and the price of such an adventure can make around $2 billion.

The main problem with the current pharmaceutical drug development model is not the time from a lab to market, but the lack of ideas resulting in cures and the high failure rate. It costs on average $2.5 billion to develop a drug. This is primarily due to a large number of failures in clinical trials. In oncology, the success rate is ~5% and Phase II is the riskiest area. In many other therapeutic areas, there are no products resulting in complete cures.

The main costs are in clinical trials because of the lack of effective in silico tools and due to the poor translation from animal models to humans. And this is where I disagree with the many other scientists in aging research. If we see 95% failure rate when taking drugs that show both safety and efficacy in mice into humans in oncology and other fields, the probability that some of the completely new drugs developed to address aging in mice, are likely to have a higher failure rate.

To address this we need two things: 1. work primarily with human data for drug and biomarker development and 2. we need a very sensitive and accurate system to perform a cross-species analysis. Therefore, our short term goal is not to necessarily shorten the time but to increase the probability of the molecule passing the clinical trials and resulting in a cure or substantial amelioration of a disease.

Once the regulation of drug approvals adjusts for the advances in AI, it may be possible to significantly accelerate the process, but right now it is important to increase the success rate.

What is your estimate, when we could expect the first powerful treatment to slow down aging appear on the market? By powerful we mean, preventing some age-related disease and extending life by 10 years? What aging process will be addressed first?

I think that there are several very powerful treatments that are already available on the market and to get the extra 10–20 years or even more we just need to devise a way to turn these into therapeutic regimens. I think that a comprehensive regimen involving metformin, targeted rapalogs, senolytics, anti-inflammatory agents, aspirin, NAC, ACE inhibitors, beta-blockers, PDE5, PCSK9 inhibitors, NAD+ activators and precursors in combination with regenerative medicine procedures and also a set of cosmetic and lifestyle interventions could easily add 20 years to our life span. And I am sure that some people are already trying these interventions on themselves.

Unfortunately, nobody is tracking this data. I also hope that some of the interventions will be developed by our team. We apply our drug discovery pipelines to identify the compounds that are much more likely to pass through clinical trials and result in substantial health benefits. We also provide a set of companion biomarkers to ensure that we do not enroll patients, who are not going to respond to therapy.

In terms of addressing the specific aging processes, we are addressing the three low-hanging fruits. We found new mechanisms for clearing out the senescent cells and manipulating a few other cell-states in a very creative way and in a tissue-specific manner. We also found the new tools to go after several types of fibrosis. And finally, we have a few molecules to induce the endogenous repair processes.

Over the past few years, we saw many high-net worth individuals announcing their intent to focus on aging. Google launched Calico, Facebook announced a program to cure all diseases within this century, Peter Thiel is supporting the SENS Foundation and sponsoring blood transfusions from young to old patients. What do you think of this trend?

It is not surprising that the majority of the high net worth individuals supporting longevity research come from IT. In just three decades they transformed our lives beyond recognition. What is surprising is that there is so few of them and that they hire “old school” scientists and business people to run their initiatives instead of actively getting involved. The US government alone spends over $40 billion dollars annually on biomedical research through the NIH, NSF, DOE and other funding bodies, with just the National Institute on Aging spending over $1 billion every year for many years.

While we see many promising results from these government-funded initiatives, the contributions Google, Facebook, Oracle, and others could make if they really focused their efforts and applied their own minds to aging research, could be much greater and more disruptive. Putting slightly more resources in the hands of the scientists, who are doing science for the sake of science is not going to result in any dramatic changes or acceleration.

What we need is Facebook and Google brains working on the problem of aging in a disruptive way. And that is why I think that even within the Google universe, Verily is likely to contribute more to extending productive longevity than Calico. Unfortunately, they are not positioned as an anti-aging company.

As the high net worth individuals (HNWI) go, I really like Jim Mellon’s approach. Before he announced his intention to invest in the longevity business, he personally went on a long road trip visiting dozens of laboratories in the US and Europe and wrote a book called “Juvenescence”, where he described his vision and invited other people to invest. He really took the time and took a deep dive into the industry, technology, and people before making the bets. I think that the other HNWIs should follow Jim’s example each in their unique way. I am not sure about the space race, but a race for longevity among the HNWIs could transform our lives for the better.

Conclusion

We wish to thank Dr. Zhavoronkov for taking the time to do this interview with us and for providing such detailed and interesting answers about the exciting world of A.I. and research.

You may also be interested to learn that Dr. Zhavoronkov and the team he is part of are currently hosting the Mouseage project on lifespan.io, a project that aims to create a photographic biomarker of aging in mice using the power of machine learning. The goal of this project is to help speed up aging research and save the lives of animals. You can make a real difference by donating, helping them to create a valuable research tool and improve the lives of animals sooner. Visit the Mouseage campaign today and show your support.

Literature

[1] Buzdin, A. A., Zhavoronkov, A. A., Korzinkin, M. B., Venkova, L. S., Zenin, A. A., Smirnov, P. Y., & Borisov, N. M. (2014). Oncofinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data. Frontiers in genetics, 5, 55.

[2] Artemov, A., Aliper, A., Korzinkin, M., Lezhnina, K., Jellen, L., Zhukov, N., … & Buzdin, A. (2015). A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation. Oncotarget, 6(30), 29347.

[3] Aliper, A., Plis, S., Artemov, A., Ulloa, A., Mamoshina, P., & Zhavoronkov, A. (2016). Deep learning applications for predicting pharmacological properties of drugs and drug repurposing using transcriptomic data. Molecular pharmaceutics, 13(7), 2524-2530.

Removing Aging Cells With a New Class of Senolytic Drug

The new research work on senolytic drugs by Baar et al. uses a rationally designed molecule that selectively targets senescent cells in vivo, both in an accelerated aging mouse model, and in normally aged mice as well, with few if any side effects [1]. Senolytics are a new class of potential anti-aging drugs that function by specifically killing senescent cells through apoptosis.

The phenotypic changes seen in non-dividing senescent cells, such as the senescence associated secretory phenotype (SASP), can in turn aberrantly influence nearby cells, leading to chronic inflammation and other changes that are detrimental to an organism [2].

Senescent cells

Senescent cells normally destroy themselves via a programmed process called apoptosis and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and build up.

By the time people reach old age, significant numbers of these senescent cells have accumulated in the body, and inflammation and damage to surrounding cells and tissue. These senescent cells are one of the hallmarks of aging and play a central role in the progression of aging [3-4]. Senolytics focus on the destruction of these stubborn “death resistant” cells from the body in order to reduce inflammation and improve tissue function.

It has been demonstrated that senescent cells can be cleared selectively by targeting anti-apoptotic proteins Bcl-2 and Bcl-x, using a number of different inhibitors, leading to improved tissue function in mice [5-8].

A new pathway to trigger apoptosis

The molecule in the Baar et al study instead functions by disrupting the interaction between Foxo4 and p53, leading to p53 mediated apoptosis (cell death). The authors have shown that this interaction with Foxo4 inactivates p53 and is restricted specifically to senescent cells.

This leads to cell cycle arrest and an inhibition of apoptosis. The molecule itself consists of a small peptide of Foxo4, consisting of D-amino acids in a retro-reversed sequence, fused to an HIV- Tat domain. The D-amino acids block proteolysis of the compound while the HIV-Tat domain functions as a cell penetrating peptide, enabling the molecule to transverse plasma membranes.

Conclusion

There are of course many follow up experiments that need to be done. Are there truly no side effects? Can this or a similar drug work well in humans? Also, what are the long-term consequences of clearing senescent cells? It is known that senescent cells do play a positive role in promoting tissue repair [9]. Will stem cell replacement be required for the long-term maintenance of organ function?

All in all, however, this latest work is a truly significant step forward in the development of a feasible senolytic therapy and further validates the hypothesis that the clearance of senescent cells can promote improved organ function.

Literature

[1] Baar MP, et al. “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.”Cell. 2017 Mar 23;169(1):132-147.e16. [2] Davalos, Albert R. et al. “Senescent Cells as a Source of Inflammatory Factors for Tumor Progression.” Cancer Metastasis Reviews 29.2 (2010): 273–283. PMC. Web. 10 Jun. 2010. [3] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217. [4] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. [5] Zhu, Yi et al. “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.” Aging Cell 14.4 (2015): 644–658. PMC. Web. 14 Aug. 2015. [6] Chang, Jianhui et al. “Clearance of Senescent Cells by ABT263 Rejuvenates Aged Hematopoietic Stem Cells in Mice.” Nature medicine 22.1 (2016): 78–83. PMC. Web. Jan. 2016. [7] Wang, Yingying et al. “Discovery of Piperlongumine as a Potential Novel Lead for the Development of Senolytic Agents.” Aging (Albany NY) 8.11 (2016): 2915–2926. PMC. Web. 19 Nov. 2016. [8] Zhu, Yi et al. “Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl‐2 Family of Anti‐apoptotic Factors.” Aging Cell 15.3 (2016): 428–435. PMC. Web. Jun. 2016. [9] Lujambio A. To clear or not to clear (senescent cells)? That is the question. BioEssays. 2016;38(suppl 1):S56–64.  

Reprogramming Brain Cells Offers Hope for Parkinson’s

Parkinson’s disease is one of the most well known of the neurodegenerative diseases. The symptoms include tremors and loss of motor control, which are caused by the loss of dopamine producing neurons in the brain. In fact, most of us lose these neurons as we age, but to a lesser degree. Parkinson’s sufferers have a genetic vulnerability, and so lose these neurons faster as they are less resistant to the underlying damages aging causes.

The rise of the stem cell field over the last few decades has given researchers hope that the lost dopamine-producing neurons might be replaced. Replacing lost neurons in this manner would potentially allow us to bypass the complexity and myriad factors contributing to their loss.

Therefore finding a way to replace what is lost has become somewhat of a holy grail in the stem cell field. There have been a number of attempts since the 1980s to deliver stem cells to the brain to replace those lost; however, there may be a more practical solution to the problem.

Exciting new approach to replacing lost neurons

This week saw researchers announce a promising new approach to Parkinson’s by the use of cellular reprogramming[1]. The team lead by Ernest Arenas used a cocktail of four transcription factors to reprogram support cells inside the brain. The research team placed the reprogramming factors into a harmless type of lentivirus and injected them en masse into a Parkinson’s disease model mice.

The viruses infected support cells in the brain known as astrocytes (support cells that regulate the transmission of electrical impulses within the brain) which are present in large numbers. The lentiviruses delivered their four-factor payload to the target cells, changing them from astrocytes into dopamine-producing neurons.

Within three weeks, the first cells had been reprogrammed and could be detected, and after fifteen weeks there were abundant numbers of dopamine-producing neurons present.

This is good news indeed, as it also confirms that once reprogrammed the cells remain changed and stable and do not revert back into astrocytes. Excitingly, five weeks after their injections, the mice which previously had an impaired gait due to Parkinson’s, walked normally just like healthy mice do. This suggests that direct in-situ reprogramming of brain cells has the potential to become an effective approach to treating Parkinson’s.

Conclusion

As always in medical research, we should temper our enthusiasm: the road to success is always a long one, with many unexpected turns along the way. Whilst progress is being made and a number of research teams are working on finding the holy grail of stem cell research, it will almost certainly be a number of years if not decades before we see these results translated to humans.

There is much more work to be done, and whilst we should be mindful that research takes time, we should remain hopeful that one day science will beat Parkinson’s.

Literature

[1] di Val Cervo, P. R., Romanov, R. A., Spigolon, G., Masini, D., Martín-Montañez, E., Toledo, E. M., … & Sánchez, S. P. (2017). Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model. Nature Biotechnology, 35(5), 444-452.

New Drug to Slow Aging Heading to the Clinic

The biotechnology company PureTech are moving towards human clinical trials with a new therapy that may slow down the aging process and combat age-related disease. The company has licensed two new drug candidates, derivatives of the drug Rapamycin, from pharmaceutical giant Novartis. PureTech have recently announced a joint venture with Novartis called resTORbio and are moving to clinical trials of the new drugs later this year.

The aim of the first test phase is to see if the new drug can rejuvenate the immune system of aged people, a key reason why we lose the ability to resist diseases as we grow older. Novartis already successfully completed two Phase IIa studies, exploring the immune-enhancing potential of mTORC1 inhibitors in elderly patients. resTORbio plans to build on those findings and start a Phase IIb study, with the two licensed candidates later this year.

Excitingly, the firm has also said that it plans to extend the program to other age-related disorders in the future. “mTORC1 inhibitors could lead us to a new paradigm for treating several aging-related conditions,” said Chen Schor, a PureTech senior executive involved in the resTORbio program. “We have a robust clinical development plan for the first indication and plan to explore the program across multiple aging-related diseases.”

PureTech has set aside $15 million to invest in resTORbio, which will give it about a 58% stake in the new venture; it also has the option to invest another $10 million, which would take its holding in resTORbio to 67%. This is a serious amount of money and a sign that things are starting to change in the world of rejuvenation biotechnology.

It’s all about the mTORC1

Rapamycin is a well-known immunosuppressant and is a substance originally discovered in soil bacteria native to Rapa Nui in Easter Island. Rapamycin blocks the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, which regulates both intracellular and extracellular cell signaling and is a central regulator of nutrient sensing, protein synthesis, cell growth, cell proliferation, and cell survival. When mTORC1 signalling is blocked by rapamycin, it pushes the cells into a survival mode which causes them to live longer.

Rapamycin has been the focus of a number of studies due to its consistent ability to increase lifespan in other species including flies, worms, and rodents. Mice given rapamycin see an average increase of twenty-five percent to their maximum lifespan, which is very impressive indeed.

The key point about rapamycin is that these results are consistent and easy to reproduce, a very important thing in research. Numerous studies have shown rapamycin can influence lifespan and whilst there is currently a study underway in Seattle to see if it extends the lifespan of dogs, there have yet to be any studies in people.

Based on Rapamycin

The new drug is a variant of rapamycin, known as a rapalog, and is sold by Novartis under the brand name Afinitor, though it is more commonly known as Everolimus. The first step for resTORbio will be to use the drug to reverse immunosenescence, or what most people describe as the decline of the immune system.

As we age, the immune system becomes increasingly run down and unable to defend against pathogens, which eventually leads to age-related diseases. The decline of the immune system is a big reason why cancer risk soars from age sixty, for example – because there are fewer and fewer immune cells seeking out and destroying cancer cells.

The first human trials are focused on seeing if this age related decline can be reversed, and appear to include restoring populations of T cells whose levels decline in age.

Joe Bolen the PureTech Health CSO said “Consistent with our strategy of addressing the impairments of the brain, gut, and immune systems, targeting the mTORC1 pathway offers us a compelling opportunity to address conditions impacting these adaptive systems.” He further added “Impairment of adaptive and innate immune system robustness underlies age-associated immunosenescence. Inhibition of the mTORC1 pathway has proven to be effective in re-establishing T-cell composition and function, which in turn can revitalize immune homeostasis.”

The reason why anti-aging drugs are traditionally not developed

Historically, no drugs have been developed to target the aging processes; there are a number of reasons for this. Firstly, it is clinically very difficult to prove efficacy of life-extending drugs in humans, as relatively speaking we live for a very long time; it is easy to conduct tests in mice, rats, worms, and yeast, as they live far shorter lives.

Fortunately, the development of increasingly better biomarkers has started to improve this situation. Reasonable projections can be made for potential lifespan increases based on standard survival curves referenced against biological age. The way to solve this problem is to create comprehensive ways of measuring biological age and a number of companies are engaged in exactly that.

Secondly, the field of life extension has traditionally been viewed with extreme skepticism and was (and still is) haunted by quacks and snake oil salesmen hindering the legitimate researchers. It is hard for most people to tell the difference between a charlatan and a real researcher, so this leads many people to consider the entire field as quackery not to be taken seriously.

Thankfully, this has started to change in recent years, as more and more respected researchers have gotten involved and the results have started mounting up to support the idea. Groups like the SENS Research Foundation have existed for over a decade and have been advocating a repair approach to aging, and whilst it has been a slow uphill battle to change perceptions about aging, the tide is starting to turn in the face of ever more promising research.

Thirdly, current regulations mean aging cannot just be generally targeted, as it has various processes and none of them are officially accepted as a disease even though they lead to age-related pathology. This is the biggest problemm and whilst pressure to classify aging as a disease has increased in recent years, it will be some time before such things are potentially accepted. Solving this will be a long and hard slog to convince regulatory authorities combined with mountains of scientific evidence to support it.

Until then, companies are opting to get age-related therapies through the regulatory gauntlet by targeting the aging mechanisms but stating a particular disease condition. This is why resTORbio will focus on immunosenescence, as it is a well-documented phenomenon which can be easily measured to determine efficacy, and can be related to specific diseases.

Conclusion

Until the idea of preventative repair strategies directly targeting the aging processes becomes mainstream, companies will have to continue jumping through regulatory hoops in order to get these new drugs and therapies into practice.

Part of changing established ideas and creating that shift in paradigm is supporting fundamental and breakthrough research through grassroots fundraising. The more scientific evidence to support a repair approach to aging diseases, the sooner established ideas will change.

This is the power of a grassroots movement and what we do now could have huge impact in the years to come. We are hoping to play our part in this at LEAF using the Lifespan.io platform to fundraise for science and taking part in activism and education.

In closing, we are very pleased to hear the news that yet another large, well-funded company is getting involved in the science of longevity, and we can only hope that this encourages others to do the same.

 

Scientists Reverse DNA Damage in Mice. Human Trials are Next.

DNA is a critical part of cells, the instruction manual for building them. While DNA is well protected within the cell nucleus, damage does occur; therefore, DNA repair is absolutely essential for cell function, cell survival, and the prevention of cancer.

The good news is that cells can repair damaged DNA, but the bad news is that this ability declines with aging for reasons that are not yet fully understood.

An exciting new study by researchers led by Dr. David Sinclair at Harvard Medical School shows a part of the process that enables cells to repair damaged DNA, and it involves the signaling molecule NAD. This study offers insight into how the body repairs DNA, how DNA damage relates to aging, and why our repair system declines as we age. Before we get into the new research study, let’s take a look at how DNA damage relates to aging and what NAD is.

Genomic instability: a driver of aging?

The stability and integrity of our DNA is challenged on a daily basis by various external physical, chemical, and biological agents as well as by internal threats such as replication errors and reactive oxygen species.

Some aging theories, such as the Hallmarks of Aging, implicate DNA damage as one of the primary driving processes of aging, as it contributes to genomic instability [1]. Various premature aging diseases such as progeria are the consequence of accumulated DNA damage; however, the relationship between progeria and normal aging is as yet unresolved. This is partly due to the fact that the different progeroid syndromes only manifest certain aspects of aging seen in normally aging people.

What is NAD?

Nicotinamide adenine dinucleotide (NAD) is a dinucleotide, meaning that it consists of two nucleotides joined by their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide. NAD is found in an oxidized form and a reduced form, abbreviated as NAD+ and NADH respectively.

As part of its role in metabolism, nicotinamide adenine dinucleotide supports redox reactions, which involve moving electrons from one reaction to another. The transfer of electrons is the primary function of NAD, but it also has other roles.

Found in every cell in our body, NAD helps to suppress genes that accelerate the aging process and is a fundamental part of our metabolic system. NAD is associated with the sirtuins, which are closely linked to longevity in mammals and other organisms. Its control over cell damaging oxidation is also well documented. NAD declines during the aging process due to being actively destroyed by inflammatory signaling, as shown in a 2013 study by Schultz and Sinclair [2].

So, what’s the big news?

This new study demonstrates a previously unknown role for the NAD signaling molecule as a master regulator of protein-to-protein interaction during DNA repair. It also gives us valuable insight into why the body’s ability to repair DNA damage begins to fail as we age [3].

These experiments conducted in mice demonstrate that treatment with a NAD precursor known as nicotinamide mononucleotide (NMN) can mitigate and resist age-related DNA damage as well as the damage resulting from exposure to radiation. While there is no guarantee that these results will translate from mice to humans due to differences in biology, if they do, potential therapies may be the result.

Building on previous research

David Sinclair and his team already demonstrated that NMN can extend the lifespan of mice in a previous study [4] and reverses loss of mitochondrial function with age [5]. The team began this new study by examining the various proteins and molecules that they believed were involved in the aging process.

They knew that NAD, whose levels fall with age, increases the activity of the SIRT1 protein (one of the Sirtuin family) and can delay some aspects of aging, extending the lifespan of yeast, flies, and mice. They also knew that SIRT1 and PARP1, a protein that is involved in DNA repair, both consume NAD during their activation.

The team also looked at a protein called DBC1, a common protein found in humans and many other organisms from bacteria upwards. Studies had shown that DBC1 is able to inhibit the activity of SIRT1, so they believed that it might also influence PARP1, given their similar roles, and wanted to see if it was connected to NAD. It turns out that they were correct, and the study revealed this link.

The research group tested the relationship between the three proteins by measuring protein-to-proteins interaction within human kidney cells. They discovered that PARP1 and DBC1 actually bond strongly to each other, but when NAD levels increase, that bonding is reduced.

Simply put, the more NAD in a cell, the fewer bonds DCB1 and PARP1 can form, freeing up PARP1 so it can repair damaged DNA. They also took this further, inhibited NAD and noted the number of DBC1 to PARP1 bonds increased. This shows that reduced levels of NAD strongly influence the ability of cells to repair DNA damage.

These findings suggest that as NAD falls during the aging process, the less NAD there is to prevent DBC1 and PARP1 bonding, which is harmful to DNA repair. The result of this ultimately causes DNA damage to go unrepaired and accumulate over time, leading to cell damage, mutations, loss of tissue, cell function, and organ failure.

Getting down to the nitty-gritty

That in itself was interesting enough to have discovered this previously unknown function of NAD, but the researchers wanted to understand exactly how NAD was doing this. To find out how NAD prevents DBC1 from bonding with PARP1, they examined a region of DBC1 known as NHD.

NHD is a pocket-shaped structure common to around 80,000 different proteins in a huge number of species, and its function has been a mystery to scientists. The team showed that this NHD region is a NAD binding site, and in DBC1, NAD binds to this region and prevents DBC1 from bonding with PARP1 to prevent DNA repair.

Interestingly, NHD is so common in across species it suggests that this NAD binding might play a similar role preventing harmful protein interactions in many species, including humans.

Moving to mice

Next, the researchers treated old mice with NMN, but before they did they checked the protein levels in the mice. As predicted, the old mice had lower levels of NAD in their livers, as well as lower PARP1 levels and a larger number of bonded PARP1 and DBC1 proteins.

However, once given NMN in their drinking water for just one week, the old mice showed significant improvement in NAD and PARP1 levels. Tests showed the NAD levels in the livers of the old mice increased similar to those observed in younger mice. PARP1 levels were a similar story and PARP1 and DBC1 bonded proteins were reduced. The researchers also recorded a reduction in biomarkers of DNA damage suggesting that DNA repair had been improved.

Finally, the researchers exposed mice to radiation to damage their DNA. They discovered that mice treated with NMN before radiation exposure showed lower levels of DNA damage. The mice also did not display the characteristic changes to blood counts, such as changes to lymphocyte and hemoglobin levels, typically seen after radiation exposure. Interestingly, mice treated after radiation also enjoyed similar protective effects from NMN treatment.

Conclusion

Human trials with NMN are anticipated to begin within the next six months according to the researchers, and the potential discoveries are significant for our understanding of the biology of aging.

In closing, the results reveal a previously unknown mechanism behind DNA repair and cell death caused by DNA damage. Should further animal studies and human clinical results confirm the findings, this might pave the way for therapies that repair DNA damage due to radiation exposure from radiotherapy and the environment along with possibly treating age-related decline.

As always in science, we should remain optimistic, but further studies are needed before we can draw any final conclusions. We look forward to seeing the results of clinical trials in the near future.

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217. [2] Schultz, M. B., & Sinclair, D. A. (2016). Why NAD+ Declines during Aging: It’s Destroyed. Cell metabolism, 23(6), 965-966. [3] Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J., … & Aravind, L. (2017). A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science, 355(6331), 1312-1317. [4] North, B. J., Rosenberg, M. A., Jeganathan, K. B., Hafner, A. V., Michan, S., Dai, J., … & van Deursen, J. M. (2014). SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal, e201386907. [5] Gomes, A. P., Price, N. L., Ling, A. J., Moslehi, J. J., Montgomery, M. K., Rajman, L., … & Mercken, E. M. (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624-1638.

Some people think only the rich will afford life extension.

Will Increased Lifespans Be Only for the Rich?

The concern that rejuvenation biotechnologies might cause social disparity and further widen the gap between rich and poor is one of the most commonly raised ones, probably second only to concerns of overpopulation. Like many others, this concern may appear valid at first, but it does not survive careful analysis.

Anti-aging sticker shock

The underlying assumption of this argument is that rejuvenation therapies would be so very expensive that only rich people would be able to afford them, thus fracturing the world into ever-young, ever-healthy rich people and the poor, sick, old people with no access to these technologies. It is very likely that rejuvenation therapies will be quite expensive (at least initially) due to a number of factors.

However, before we delve deeper into the details of this discussion, let’s remind ourselves of an important but possibly understated fact: rejuvenation biotechnologies are life-saving medical treatments that are meant to prevent age-related diseases and allow people to maintain good health throughout their lives. In this sense, they are no different from antiviral or cancer therapies, which are currently prescribed and administered by doctors in appropriate healthcare facilities. So, just the same as any other life-saving treatments, the price is irrelevant in the face of the benefits that they would confer to us, and it is certainly not a valid reason not to develop them.

However, even if we can initially assume a high cost for rejuvenation biotechnologies, we need to keep in mind that new technologies generally start off as very expensive and eventually become affordable and widespread. For instance, it took only 15 years for the full genome sequencing cost to drop from $100 million to $300, making personalised medicine reality globally.

costpergenome2015_4

Fig 1. The Cost of Sequencing a Human Genome change, 2001-2015. Source: National Human Genome Research Institute

In the field of medicine, there are several other examples of this same trend of falling cost and prices. The drug metformin, which is used for the treatment of type 2 diabetes (and probably the first drug to slow down aging in healthy people, which is currently the subject of the TAME clinical trial), was initially expensive but eventually its price plummeted to a few dollars. Its price fell from $1.24 per tablet in 2002 to 31 cents in 2013. The infographic below shows some other examples of drugs that were once expensive and have subsequently fallen in cost.

capture

Similarly, improvements in technology have drastically reduced the costs of research diagnostics, and the advent of remote technology has allowed a cost reduction for both patients and hospitals, as specialists can be contacted at a distance. For example, hospitals do not need to have radiologists on location all the time. Instead, they can instead remotely send them patient data for analysis and thus only pay for each individual service; this, in turn, implies potentially cheaper services for the patients as well.

Even gene therapies, stem cell therapies and immunotherapies may soon become cheaper, less time-consuming, and consequently more widely available thanks to innovations such as this new semi-automated benchtop system, which produces modified cells in sufficient numbers very rapidly at lower cost, or automated systems for cell therapies and immunotherapies with similar production streamlining and potential cost reduction [1-5].

Outside of the field of medicine, a classic example of dropping prices is that of computers and electronics. At the beginning of the computer age, computers were huge pieces of machinery with very limited capabilities, and only few institutions in the world could afford having a few of them at best. However, as technology improved, the production of computers (and that of electronics in general) has become easier, cheaper, and more efficient, to the point that today we all walk around with tiny computers—smartphones—in our pockets, and these computers are hundreds of times more powerful than those used by NASA to send the first people on the Moon.

Similarly, cars used to be too expensive for an average person to afford. Today, not only are cars ubiquitous and largely affordable, but even the newer, cutting-edge electric cars (for example, Tesla cars) are reaching the same price range as regular cars, despite being relatively new on the market. Another example of the high-tech sector is that of 3D printers. A mere decade ago, a 3D printer cost around $100,000; today, one can buy a good 3D printer for less than $500—a price drop of 95.5%.

Even more interestingly, this trend extends further to other areas of technology, such as the food industry. In 2013, the first lab-grown burger cost $325,000; a mere two years later, the cost had dropped to around $11. Even though the company estimates that it would take two decades to turn the burger into a viable product, other companies have recently shown confidence that this can be achieved on a much shorter time scale.

For example, SuperMeat hopes to have its first lab-grown meats available in stores in only five years, for the same price as regular meat or less. All of these examples show that technology typically becomes much cheaper as time goes by; there is no reason to believe the same would not be true of rejuvenation technologies, especially when one takes into account an extremely strong economic motivator.

Rejuvenation would be the largest industry in history

The market for rejuvenation biotechnologies would be the largest in history, and, indeed, some investors, such as billionaire investment expert Jim Mellon, are already taking notice. Every single person in the world is aging and is thus a potential customer. It is of course very likely that people who have wealth, and therefore greater means, will obtain cutting-edge technology first (as we have seen repeatedly throughout history) before everyone else. This has always been the case, and it has always been that, shortly thereafter, such technology and access has become widespread.

However, one should consider that those early adopters are playing “guinea pig” and, in effect, are paving the way for the masses and helping developers offset the costs incurred during development, as they are paying premium prices for early access to these technologies.

Socio-economic considerations

If, for the sake of argument, we assume that rejuvenation biotechnologies could somehow be an exception to the trend of falling prices in technology, we would need to decide whether people ending up paying for their own rejuvenation therapies is more of a realistic scenario than governments subsidizing the treatments, partly or wholly.

The majority of countries in the world have universal healthcare systems that take care of their citizens’ or residents’ health needs either for free or for a nominal fee. These costs are offset by taxes, which ensure the health service is able to provide this level of care to all.

Fig 2. 2009 Countries with universal Healthcare Source: wikimedia

Other countries, particularly the United States, do not have a universal healthcare system; citizens or residents of such countries generally have private health insurance to cover their medical expenses, and the coverage of each insurance plan may vary substantially, depending on what each individual subscriber can afford.

In many ways, aging can be considered to be a chronic, progressive, and fatal disease (indeed, some researchers do [6]) of the type that insurance companies would likely not be willing to pay medical expenses for. However, we should take into account that its progression is remarkably slow. It generally takes decades for age-related diseases to manifest, so it would probably make little sense for people under forty years of age to include rejuvenation treatments in their health insurance. As a matter of fact, the very nature of the problem may call for an entirely different insurance strategy.

Presently, insurance policies are drawn up to cover the cost of potential risks that might lie ahead; this is the very reason why more likely risks make for more expensive policies and vice-versa. One is not guaranteed to get all age-related diseases—simply because one or few of them manage to kill us before we can get the others—but comprehensive, preventative rejuvenation necessarily needs to address all aspects of biological aging that may lead to any such ailments; in this sense, aging is a disease that we all suffer from, and we will all suffer from each of the age-related diseases if we live long enough.

Therefore, aging is not a potential risk but rather a certain fate that will strike each of us differently, depending on individual circumstances. While the market share of each insurance company offering rejuvenation policies would be huge, such policies could not logically treat aging in the same way they treat potential risks. An insurance company will pay for a customer’s stolen car—or medical expenses for a certain disease—if and when the car has been stolen—or when the disease has struck.

However, aging is a lifelong process that needs to be addressed in a preventative fashion [7] [8]; at no specific point could we say “aging has struck the patient now, but not before.” This suggests that private insurance may not the be right way to go; instead, we should consider this matter from the point of view of the government.

Health costs in the current system are unsustainable

Health expenditures for the elderly currently constitute a considerable burden on a country’s economy. Although the elderly have already contributed wealth to society when they were younger, they often stop doing so when they retire. Furthermore, they receive a pension from the government and will do so for the rest of their lives. While, in theory, pensions should already have been paid for by the elderly themselves with their work earlier in their lives, things are quite different in practice, and some countries are already increasing the retirement threshold further.

This is an unsustainable strategy, because barring radical interventions—such as rejuvenation therapies—there is a point past which elderly people simply are not healthy enough to work. As a matter of fact, the cost of medical expenses for the elderly grows dramatically each year, and it is also to be noted that geriatric treatments lead to no significant results, both in terms of overall individual well-being and fitness for work, and they become increasingly less effective as the patients grow older. As a result, most individuals produce no wealth and their deteriorating health causes increasingly significant expenses during the last year or two of life and further strain on the economy [9].

The desired result of rejuvenation therapies leads to a much better scenario. If rejuvenation therapies are reapplied with proper timing, no individual would ever reach a state of age-related decay and poor health that could make him or her unfit for work. Consequently, the costs of treating age-related diseases using current medicine could be reduced with the arrival of more robust therapies offered by rejuvenation biotechnology. Such rejuvenation therapies aim to prevent a plethora of diseases before they manifest, potentially saving money. However, even if the costs are the same and we are simply trading one set of medicines for another, the benefit to health, quality of life and productivity makes it more than worth it regardless.

Retirement and increased lifespans

When considering retirement in relation to rejuvenation biotechnology, we should consider the two possible scenarios that may arise. The first scenario is the simple increase of lifespan beyond the current limits – this could be a few years or even a decade or two of healthy life. The second scenario is that of negligible senescence, in which medicine allows indefinite lifespans via periodic repair of the various damages and dysfunctions aging causes. Let’s take a look at both of these possibilities and consider the benefits and changes society may encounter as a result.

Scenario 1: Increased lifespans. In a situation where additional healthy years were added to the human lifespan, an immediate benefit to society would be that people could retire later in life and continue to contribute economically and remain productive for longer. This would reduce the costs of pensions and help bolster the economy. Ultimately, in this scenario people would still retire as they already do, but later in life and with more healthy years to enjoy.

Scenario 2: Negligible senescence. In the more extreme case of negligible senescence, people would, in principle, be able to work indefinitely, regardless of their age, thus producing wealth nearly constantly. For this reason, retirement would likely change from a permanent cessation of working to the need for a break longer than a normal holiday, perhaps similar to a long-term work sabbatical. Pensions might even become optional, with workers taking sabbatical breaks from work that could last for years, allowing people to retrain and reinvent themselves.

Another remarkable benefit would be that the government would see drastically reduced costs, which are traditionally spent on pensions, as people would no longer retire in the traditional sense. It might be the case that the government would perhaps replace traditional pension schemes with sabbatical or UBI schemes to allow workers to accrue money over time to take such a break from work. If the State did not do this, then private enterprise might provide such a service.

In short, this second scenario has the potential to turn the current situation on its head—we would go from having high morbidity of age-related diseases that disable the elderly preventing them from being productive and causing major public expenses, to having productive elderly who contribute to the economy and whose health needs are little-to-no burden on it.

It’s easy to see how it would be far more convenient for any given State to pay for the periodical rejuvenation treatments of its citizens rather than maintaining the current state of affairs.

Apart from economical considerations, we must also keep in mind that, as said, rejuvenation therapies are life-saving medical treatments that prevent age-related diseases from ever manifesting. As such, ensuring their development and widespread access is among the objectives of WHO, according to its Constitution. The WHO Constitution says that each government is responsible for the health of its residents, and the attainment of the highest health standards is the very objective of WHO itself.

The WHO definition of ‘health’ is a ‘state of complete physical, mental and social well-being and not merely the absence of disease or infirmity’. Rejuvenation therapies match this definition perfectly: they would eliminate age-related diseases entirely and enable people to enjoy a normal life regardless of their age, without the limitations currently imposed on the elderly by their constantly declining health. They would improve the physical, mental, and social well-being of all people.

The WHO Constitution further states that ‘[t]he enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, political belief, economic or social condition. In other words, because of the health standard improvements they would cause, rejuvenation therapies would be a basic right of everyone, and both local governments and WHO would have a responsibility to do all in their power to make sure this right is respected. (As a side note, this last paragraph of the Constitution would be better if it said that no distinction of age should be made either).

If not everyone can have it, then no one should have it?

Thus far, we’ve argued that while rejuvenation therapies may well be expensive at the beginning, they would be government subsidized and would likely become cheaper and cheaper as the underlying technology improves. However, what if this prediction were wrong?

If everyone was supposed to pay for their own, expensive rejuvenation, then being indefinitely young would indeed be only for the rich, and the rich-poor gap would become even worse than it already is. It’s easy for people in developed countries to feel guilty about the privileges they have with respect to people in developing countries. Everlasting youth would be quite something to feel guilty about if not everyone had it. Not developing rejuvenation might thus prevent first-world people from having yet another thing to feel guilty about, but that’s all it would do; it would not help third-world people in any way.

Let’s assume that we found out that rejuvenation would be so expensive that only very rich people could afford it, and, for this reason, we decided not to develop it at all. How would this affect the poor? We didn’t develop rejuvenation, so nobody got it, including the poor. If we had developed rejuvenation, the poor wouldn’t have gotten it anyway, because it would have been to expensive for them to afford. So either way, nothing changed for the poor, and they certainly didn’t benefit from rejuvenation not existing.

What about the rich? If we didn’t develop rejuvenation for fear of increasing the gap between rich and poor, then the rich – like the poor – would keep getting sicker as they aged. Surely this didn’t make the gap larger, but it didn’t make it any narrower either. Not developing rejuvenation (or any other new technology, for that matter) doesn’t help the poor, and doesn’t close the rich-poor gap. If we think about it, we see that simply closing the gap isn’t enough. What really matters is how we close it. If developed countries gave up on all their comforts and wealth and became like the developing countries, then the gap would be closed, but no one would benefit from it. The only sensible way to close the rich-poor gap is making the poor better off, not the rich worse off.

Conclusion

So, no, not developing rejuvenation isn’t the way to go. Rejuvenation, like anything that can improve human life, needs to be developed. The concern that rejuvenation might become a privilege of the rich only is legitimate, but the way to avoid this scenario is not to give up on rejuvenation entirely but rather to work hard to ensure that it becomes as widespread and affordable as basic medicine.

Each and every one of us has the power to do something in this sense – be it by working on the necessary science, supporting it financially, lobbying to change relevant regulations, or even just spreading the word and let everyone know about this possibility. Our journey towards a future free from age-related diseases for everyone will be as short – or as long – as we will make it.

Literature

[1] Konagaya, S., Ando, T., Yamauchi, T., Suemori, H., & Iwata, H. (2015). Long-term maintenance of human induced pluripotent stem cells by automated cell culture system. Scientific reports, 5.

[2] Rafiq, Q. A., Twomey, K., Kulik, M., Leschke, C., O’Dea, J., Callens, S., … & Murphy, M. (2016). Developing an automated robotic factory for novel stem cell therapy production. Regenerative medicine, 11(4), 351-354.

[3] Chen, V. C., Ye, J., Shukla, P., Hua, G., Chen, D., Lin, Z., … & Hsu, D. (2015). Development of a scalable suspension culture for cardiac differentiation from human pluripotent stem cells. Stem cell research, 15(2), 365-375.

[4] Conway, M. K., Gerger, M. J., Balay, E. E., O’Connell, R., Hanson, S., Daily, N. J., & Wakatsuki, T. (2015). Scalable 96-well plate based iPSC culture and production using a robotic liquid handling system. Journal of visualized experiments: JoVE, (99).

[5] Granzin, M., Soltenborn, S., Müller, S., Kollet, J., Berg, M., Cerwenka, A., … & Huppert, V. (2015). Fully automated expansion and activation of clinical-grade natural killer cells for adoptive immunotherapy. Cytotherapy, 17(5), 621-632.

[6] Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. Frontiers in genetics, 6.

[7] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[8] Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., … & Rando, T. A. (2014). Aging: a common driver of chronic diseases and a target for novel interventions. Cell, 159(4), 709.

[9] Scitovsky, A. A. (2005). “The High Cost of Dying”: What Do the Data Show?. Milbank Quarterly, 83(4), 825-841.

Kelsey Moody – Developing a Therapy for Age Related Blindness

New medical technologies need bold researchers to make the leap from the laboratory table to hospitals and clinics, where they can improve or even save lives. Kelsey Moody, a 30-year-old scientist from Beekmantown, is one such researcher.

Kelsey is especially interested in the treatment of age-related diseases but is using a different approach. Currently, researching age-related diseases like cancer, Alzheimer’s, diabetes, Parkinson’s, and heart disease takes up huge amounts of funding; however, very few of these approaches aim to treat these pathologies at their root causes – the processes of aging – and this is why they are not successful.

His focus in the past few years has been developing an effective treatment for age-related macular degeneration (AMD), a leading cause of vision loss among people over 50.

The experimental treatment he’s working on, called LYSOCLEAR, is currently being tested for validity at Ichor Therapeutics, a startup Moody founded in 2013 when he was only a second-year medical student with a $540,000 grant received from the Life Extension Foundation. LYSOCLEAR  is based on the LysoSENS approach advocated for by the SENS Research Foundation, where Moody worked as an academic coordinator first in 2008-2010 and as a research scientist in 2012.

Both age-related and juvenile-onset macular degeneration are believed to be caused by the accumulation of waste products in the retina cells of patients. This accumulation leads to deterioration of the retina itself and eventually to vision loss. Ichor’s treatment uses special enzymes to break down one of these waste products, which is called A2E. The hope is to prevent and maybe even reverse the disease.

Moody’s company has received both public and private funds for over 3.2 million dollars, and his efforts have been praised by many experts, including Cornell Medical College ophthalmologist Szilard Kiss, Syracuse University professor Robert Doyle, and SENS Research Foundation Chief Science Officer Aubrey de Grey.

Now that LYSOCLEAR’s first efficacy tests are complete, 15 additional million dollars will be needed to move to more thorough animal testing and finally to human clinical trials. If all goes well, this may happen within the next three years.

Kelsey is a long-time supporter of the SENS approach, an approach proposing to repair the damage that the aging processes do to help maintain health and delay age-related diseases. As he said to Fight Aging! during a recent interview, one of the main reasons he chose to focus on the treatment for age-related macular degeneration is that, in his opinion, it is the SENS therapy closest to clinical implementation.

If LYSOCLEAR turns out to be successful, it would go a long way towards further validating the whole paradigm. However, AMD is not the only focus of Ichor; the company also works on acute myeloid leukemia, a type of blood cancer with low survival chances.

In addition to his ongoing studies as a Ph.D. candidate in Biochemistry and Molecular Biology through the University of Miami, Moody received an MBA from Concordia University, Wisconsin in 2013 and completed two years of medical training at SUNY Upstate Medical University.

He was also Chief Technology Officer at ImmunePath, Inc. and is currently Adjunct Faculty at Onondaga Community College and a mentor for the 20 Under 20 program at the Thiel Foundation. Kelsey’s next goal after a treatment for AMD is to go back to stem cell research, perhaps ushering new SENS treatments to the clinic.

How did you learn about the SENS approach?

I first came across SENS during an online review on regenerative medicine, and this initiated my interest in the study of human aging. At the time, I had no formal training in science. However, Aubrey’s approach made sense to me at face value, so I purchased his book to study it further.

After completing the book, I felt that I did not have sufficient knowledge to know whether or not his ideas were worthy of serious pursuit, but I was intrigued. I added a major in biochemistry and reasoned to myself that I would commit to the study of aging until such a time as it was clear to me that such a pursuit was not feasible or a worthwhile use of my time and resources.

Now, a decade later, I have graduate-level training in research, business, and medicine. While the conversation has become much more sophisticated, the original plan holds true. I have not reached a point where I believe SENS is unworthy of serious study.

I have focused my company on translational research because I believe that this is the area where we can have the greatest impact and where the largest deficits exist among the various longevity organizations, both nonprofit and commercial.

How easy (or difficult) would it be to adapt LYSOCLEAR to target different types of waste products in lysosomes of different tissues?

The idea of LYSOCLEAR is based on enzyme replacement therapy, which has already been used extensively in a clinical setting for the treatment of lysosomal storage diseases. In principle, the concept of “upgrading lysosomes” can be extended to numerous diseases of aging. The challenge is almost always in identifying ways to efficiently and specifically target the payload to its destination.

This is somewhat easier when your target cells are well studied and express receptors known to facilitate efficient targeting, such as monocytes or (in our case) retinal pigmented epithelial cells. It is a harder technical problem for other tissue types. Broadly, though, I am optimistic that this approach can be repurposed for other diseases, either by our team or others.

What other age-related diseases could be prevented or cured by clearing the waste from lysosomes?

Atherosclerosis immediately comes to mind, and SENS Foundation has funded research to identify enzymes capable of degrading plaque components, such as 7-ketocholesterol. There is a growing body of research linking lysosomal dysfunction to a number of neurological diseases, but I am not up to date on that research, so I’ll refrain from speculating.

LYSOCLEAR may be the first SENS therapy to make it to the clinic. What do you think might be the next one?

There seems to be a lot of good work and focus on delivering senolytic drugs to the clinic. Depending on how you define “SENS therapy” (i.e. based on the SENS concept or spinning out of SENS Foundation directly) I would imagine the next therapy to be in this field.

Can you tell us more about your work on acute myeloid leukemia? Do you base your approach to this disease on the OncoSENS paradigm, or is it something different?

This is an entirely different project. Some years ago, a paper was published that stated rats who were fed a nano compound called buckminsterfullerene had a doubling of their lifespan as compared to controls. However, this initial work was not a lifespan study. It was a chronic toxicology study, and the rats just happened to be allowed to live out their lives. It was underpowered and not designed as a proper lifespan study.

Given the striking apparent effect, a number of donors and investors have expressed an interest in seeing more work done in this space. However, testing this and related compounds to make mice or rats live longer does not constitute a viable translational path. We have obtained data showing that buckminsterfullerenes could be effective for treating various types of cancer or perhaps for reducing the adverse side effects from chemotherapy and radiation therapy.

Our interest is to test buckminsterfullerenes for longevity properties, but we need a disease indication that is firmly grounded in reality (i.e. acute myeloid leukaemia) to accompany our moonshot (an anti-aging drug).

In the past few years, senescent cell clearance has been a hot topic in the field of geroprotection. Would you like to work on this type of treatment as well in the future?

There are other groups that appear to be well positioned to lead the charge with senescent cell clearance, so it is unclear to me what we might be able to contribute to this work. I suspect that our attention will likely be applied towards other areas once our LYSOCLEAR program is in the clinic.

What are the main obstacles you have met at the early stage of your project? How could the general public and active supporters eventually help aging researchers the most?

The recurring challenge I see in the aging space is that the overwhelming majority of “anti-aging” researchers have little to no formal scientific training or wet lab experience (and it shows), or they are basic scientists. Virtually none have translational experience – that is, experience moving benchtop discoveries into a path towards commercialization.

Conversely, the translational scientists I have interacted with over the years are almost transactional, and they seem to be lacking the creativity and imagination of how new technologies could be applied to solve complex medical problems. Most of the people with ideas cannot execute, and most of the people who can execute lack vision.

We try to address this issue as a company by having one foot firmly in the fringe and the other firmly in the mainstream. For example, about half of our staff are futurists with a passion for anti-aging and SENS, but we balance that with experienced pharmaceutical professionals who keep us grounded and focused on actionable discoveries and a legitimate translational strategy.

Likewise, all of our drug development programs include a far-reaching “moonshot” opportunity but also a highly conservative disease indication.

Do you have any closing thoughts for the readers?

In my mind, the most important thing the public and active supporters can do to help aging research is education. I have found that a lot of supporters really approach aging science as almost a religion. A new paper comes out showing compound X improves a few biomarkers in flatworms, and suddenly people start taking that supplement.

If we want aging science to be taken seriously and become adopted as a mainstream and legitimate discipline, we need to hold the field to higher standards. That begins with top supporters becoming the most educated and vocal critics. Our company has built a transparent and open research culture.

We pursue answers to questions; we do not care about who was right and who was wrong – and everything anyone claims is a lie until it works in our hands. The result of iterating projects through such a culture is that the projects that survive have a strong basis in reality and represent viable drug development programs that have a real opportunity to work in the clinic.

We need to demand that projects we support as an anti-aging community have actionable successes and clearly defined fail points. We also need to celebrate scientists who do a good job in failing projects inexpensively and thoroughly and who don’t get caught up in the hype of poorly designed studies and anecdotes.

Conclusion

We would like to thank Kelsey for taking the time to speak with us, and we wish his company success in developing LYSOCLEAR.

The Record Lifespan of 122 Years Could Be Surpassed

Today, February 21, is the birthday of Jeanne Louise Calment – the oldest verified human being ever, who managed to live an amazing 122 years and 164 days!

Jeanne was an independent and positive person, and she managed to live all alone until age 110. After a fire in her apartment, she moved into a nursing home, but even there, she was still able to take care of herself. However, shortly before her 115th birthday, she fell down a stairway and never fully recovered her ability to walk.

Jeanne Calment aged 22.Surprisingly, when Jeanne was 118 years old, cognitive tests revealed that she scored within the normal range and lacked signs of dementia. However, by that time she was physically frail and required a wheelchair.

There is no doubt that her record helped millions of people readjust their expectations of the maximum possible human lifespan. However, in the eyes of an ordinary person, living for that long in a state of age-related decline does not really sound like the life of their dreams.

Luckily, modern science is aiming for another goal: an extended period of health and youthful vitality, sometimes referred to as negligible senescence.

In multiple interventions in animals, it has been shown that by addressing the underlying processes of aging in young or middle-aged animals, we can help them maintain their health and activity; now, research efforts are focused on translating the same technologies into clinical practice for humans.

If, or rather when, that happens, chronological age will no longer be closely related with biological age; aged people will potentially remain strong, good-looking, and creative.

Is this a goal worth working for? We think so.

To better understand the concept, let’s take a look at this tab comparing the features of a naturally old person and a negligibly senescent person. Of course, this is just a speculation, but it is helpful to visualize the expected results of the rejuvenation biotechnologies that are currently being developed by the SENS Research Foundation and many other research organizations around the world.

*115 years is considered by some scientists to be the maximum natural human lifespan without the application of rejuvenation biotechnologies.

As you can see, negligibly senescent people people should look, feel, and be as capable as modern young and middle-aged people. However, there is also a difference: the experience collected during 80+ years of life could potentially make people more skilled, more rational, more socially responsible, and probably more kind – just as we witness these qualities in our older colleagues and our grand parents right now. Living longer can make us more human, argues Didier Coeurnelle, one of the most active European advocates of healthy life extension, in his recent TEDx talk.

Jeanne Calment age 20.When we celebrate Jeanne Calment’s birthday, let’s remember that the most human thing to do is not just to remember the record but to try hard to surpass it. Jeanne died in 1997, so she could not benefit from the advances in aging research that are available to us now.

Knowledge about healthy lifestyle choices (healthy diet, physical activity, healthy sleep, no smoking, low alcohol consumption, active social interaction) is accessible to everyone and remains the foundation of healthy longevity. We are also getting more and more data on which drugs and supplements can promote health and help us postpone age-related decline.

More powerful therapies are on the way, but, on average, it takes up to 17 years for new drugs and therapies to be approved. For some of the problems caused by aging, such as amyloids and protein crosslinks, there are still no effective treatments, even for mice.

That is why, if we would like to bring the aging processes under substantial medical control more rapidly, we should all consider giving a hand to the researchers. Crowdfunding for fundamental studies on aging, supporting more early-stage biotechnology startups developing preventive therapies, and advocating the need to switch to preventive medicine are the best ways to foster progress.

During the last years of her life, Jeanne used to say, “I have only one wrinkle… and I’m sitting on it.” Doesn’t it look like good health and youth is the real dream of a supercentenarian?

Old lady looking sad

Age-Related Blindness Drug Moving to the Clinic

The development pipeline for new drugs and therapies is a long one, and, on average, it can take up to 17 years to research, test, and bring a new drug to market [1]. The reasons for this are myriad and complex, and they include the demanding test phases required for safety and efficacy, preclinical tests, regulatory paperwork, and the need to raise funding to pay for the increasingly higher costs of R&D that accompany such projects.

In 2016, a new study of R&D costs estimated the cost of developing a new drug to be $2.558 billion. This figure per approved compound is based on estimated average out-of-pocket costs of $1.395 billion and time costs (expected returns that investors forego while a drug is in development) of $1.163 billion [2]. In short, bringing a new treatment to market is hard; this is why the news about a unique treatment for treating age-related macular degeneration heading to clinical trials is so exciting.

Ichor Therapeutics, a biotechnology company focused on developing drugs for age-related diseases, has just announced its first major series A investment round to bring its LYSOCLEAR product for age-related macular degeneration and Stargardt’s macular degeneration to Phase I clinical trials. This product would be the first clinical candidate based on the SENS paradigm pioneered by biomedical gerontologist Dr. Aubrey de Grey.

About age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss among people over the age of 50. Over 20 million Americans and 450 million people globally [3] are affected by this condition. 85% of all cases arise from the progressive loss of photoreceptors in the macula – a part of the eye responsible for central vision. The underlying pathology of AMD is thought to be caused by the death of retinal pigmented epithelial (RPE) cells, which photoreceptors in the macula rely upon to feed and survive.

With time, different byproducts are formed that accumulate in the lysosomes of RPE cells (lysosomes are cellular structures responsible for recycling waste) and interfere with their function. One of these aggregates is A2E, a toxic compound that may play a causative role in AMD and SMD.

LYSOCLEAR is an enzyme product that can enter the lysosomes of RPE cells where A2E accumulates and destroy it. Ongoing studies suggest that LYSOCLEAR is safe and effective at targeting A2E, eliminating up to 10% with each dose. Clinical trials will test this new therapy in humans to identify the optimal dose and application regimen.

Ichor is a shining example of our mission to kick-start the rejuvenation biotechnology industry with a project that we initiated with early donor support. Led by one of our most dynamic and accomplished alumni, Kelsey Moody, Ichor is forging ahead faster than we could have dreamed. – Aubrey de Grey

For an outside observer, it may seem that such breakthroughs just happen in an instant. The truth is that there are decades of constant effort behind each event of this scale. Let’s take a short glance at the past.

A bit of background

Dr. Aubrey de Grey proposed a repair approach to treating the diseases of aging back in the 2000s. Methuselah Foundation first attempted to support scientific research on aging in 2003. In its first article, Aubrey introduced his approach to academia, naming it SENS, which stands for Strategies for Engineered Negligible Senescence [4]. SENS divides aging into seven categories of damage (including toxic protein aggregation in lysosomes) and proposes repair therapies for each of them.

By addressing the aging processes one by one, medicine could prevent and treat age-related diseases to hopefully keep people healthy and independent as they grow older. Aubrey has received more than his fair share of criticism during this time; however, he was not one to give in easily. In 2009, he co-founded the SENS Research Foundation to develop the therapies and approaches he proposed. Since then, SRF has been working tirelessly to bring the cutting edge technologies it proposes into being and ultimately to market.

Successful crowdfunding activities allowed SENS to support fundamental research in many directions. Late last year, we saw the first proof of concept for its MitoSENS program aimed at repairing mitochondrial damage with a publication demonstrating that this particular SENS technology could be practical.

The OncoSENS fundraiser in 2016 helped to launch a high-throughput screening of a library of diverse drugs to find treatments for cancers that rely on alternative lengthening of telomeres. These ALT cancers correspond to 15% of all cancers, and there is no cure for them at the moment.

Fundamental research like that promoted by SRF does not directly lead to drug development, but it enriches our knowledge base, helping to find promising candidate drugs and therapies. The next logical step is translation, in which biotech startups bring candidate therapies to clinical trials.

Luckily, as at this stage the end-product can start bringing profit, it is much easier to attract investment for its further development. Last year, biotech company Unity Biotechnology announced $116 million in Series B financing to bring senescent cell clearing therapies into human clinical trials in the next year or so. The SENS Research Foundation supported some of the key researchers behind Unity for many years, as senescent cell clearance is again another SENS therapy and part of its ApoptoSENS approach.

In 2014, Ichor Therapeutics completed a material and technology transfer agreement for rights to the concepts and research pioneered by SENS Research Foundation. Now, Ichor has opened a Series A funding round to support preclinical Investigational New Drug (IND) enabling studies and phase I human clinical trials for AMD and SMD.

The company has established a partnership with Syracuse University and obtained dedicated seed funding for the program from Kizoo Technology Ventures, SENS Research Foundation, FightAging.org, CenterState CEO, and several private investors to support its present work on LYSOCLEAR.

So, things are moving forward, and we are now seeing the first SENS therapies proposed back in the 2000s moving into clinical trials. The timeframe is about right, given the current pace of research. Hopefully, we will see Ichor succeed, as millions of people around the world will be protected against age-related vision impairment caused by AMD and SMD and will be able to live their lives to the fullest for longer. Source: LYSOCLEAR Press Release

Literature

[1] Morris, Z. S., Wooding, S., & Grant, J. (2011). The answer is 17 years, what is the question: understanding time lags in translational research. Journal of the Royal Society of Medicine, 104(12), 510-520. [2] DiMasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: new estimates of R&D costs. Journal of health economics, 47, 20-33. [3] Mariotti, S. P. Global data on visual impairment 2010. Geneva: World Health Organization; 2012. WHO/NMH/PBD/12.01. [4] De Grey, A. D. N. J. (2005). A strategy for postponing aging indefinitely. Studies in health technology and informatics, 118, 209.

Four Main Economic Implications of an Aging Population

Most of the generation born in the 1980s enjoyed watching the science-fiction adventure comedy film “Back to the Future”. The plot is built around the idea that, by using a time machine, one can go back in time to fix things that have gone wrong in order to help the present get back to normal or to improve the future.

Sadly, humanity does not have such a machine, but we have something better. Expert, evidence-based forecasts can help us understand what our future is likely to be, hence enabling us to undertake measures to make it as bright as possible.

With the global population aging rapidly, there are four main economic implications that we should take into account for reasonable decision-making: a shrinking workforce, decreasing social security contributions, increasing healthcare expenditures, and an insufficient caretaker workforce.

As Arthur Guarino, an assistant professor in the Finance and Economics Department at Rutgers University Business School, explains in his recent article for Global Risks Insights:

One key economic implication of an aging population is the strain on social insurance programs and pension systems. With a large increase in an aging population, many nations must raise their budget allocations for social security.  For example, India’s social security system presently covers only 10 percent of its working-age populace, but its system is operating at a deficit with more funds exiting than entering. In the United States, projections state that the level of social security contributions will start to fall short of legislated benefits this year. In other words, the amount of money coming into social security will lessen due to fewer contributions from workers and more funds going to an aging retired population.  In Europe, in order to fund their social security system, 24 nations have payroll tax rates equaling or exceeding 20 percent of wages. The situation is also precarious for pensions. As the global population for elderly and retired workers increases, pensions must provide more income to these recipients so that they can enjoy at least a reasonable standard of living […] […] Another key economic implication of an aging population is the increase in health care costs.  As the population ages, health generally declines with more medical attention required such as doctor visits, surgery, physical therapy, hospital stays, and prescription medicine…  …For example, in the United States, it is projected that public health expenditures will rise from 6.7 percent of GDP in 2010 to 14.9 percent in the year 2050.   This increase in health care costs will mean that nations must put more funds and human resources into providing health care while also attending to the needs of other segments of their people. With an increasing aged population, there will also be shortages of skilled labor trained to care for aged patients.  It is projected that the registered nurse workforce in the United States will see a decline of nearly 20 percent by 2020 which is below projected requirements […] […] Nations, such as China and Mexico, are expected to witness declines in their workforce from the year 2030 to 2050. Other large economies such as Japan are projected to see a 19 percent decrease in their worker population within the next 25 years followed by a 24 percent decrease over the next 20 years. Europe is also expected to see declining numbers in its workforce which will impact their chance to have a growing, competitive economy. This decline in the global workforce will lead to an increase in the age dependency ratio which is the ratio of working-age to old-age individuals. Globally, the dependency ratio in 1970 was 10 workers for each individual over age 64, but the expected ratio in 2050 is four workers for each person over 64.

Sadly, the main call for change is focused on the increase in fertility. China, Japan, Vietnam, Italy, Spain, and other countries facing a rapidly aging population are undertaking measures to encourage reproduction.

This alone, however, cannot lead to rapid improvements, because many developed countries need additional workers now and not 20 years from now; similarly, the number of people of reproductive age is small and the absolute number of births may not be high enough.

That is why it is crucial for the global community to see rejuvenation biotechnologies as an important part of the solution. If therapies to slow down the aging processes are applied to middle-aged people, this could postpone the overall health decline in the working generation and help people remain on the labor market for longer. This, in turn, would help maintain sustainable economic growth.

From mechanic to medicine: How one man became a scientist

Today, we will cover a story about how a member of our community, Mike Daniels, car mechanic turned cancer researcher, was inspired by the work of the SENS Research Foundation to address age-related diseases. What follows is an emotional, gritty but honest life story of someone who took action and is now doing amazing things in his life for science.

Firstly, can you tell us a little about yourself?

Certainly, I am a first year Biostatistics PhD student at the University of Colorado. I met my wife in 2003 from an online dating website just two days after being mobilized for the Iraq war. As a 42-year old father of two daughters, I stay in touch with my parents whom still live in Appalachia where I was raised. I am unsure if I am a contradiction or a bridge between two worlds. Listening to J. D. Vance’s Hillbilly Elegy reminds me of my roots growing up along US 23 in Eastern Kentucky.

In contrast, just yesterday, I presented a journal review to a classroom filled with intellectuals such as doctors, biologists and mathematicians. As a liberal, atheist scientist with religious, conservative family and friends, I understand why voters turned out for president-elect Donald Trump and why protesters are taking to the streets. Carl Sagan said we are nothing but a pale blue dot, a mote of dust in a sunbeam, just to put everything into perspective.

So who am I? I’m the guy who fixed your air conditioner, roofed your house, changed the spark plugs in your car’s engine, worked the production line in a food factory, defended your country during war, waited your table at your favorite restaurant and even washed your dishes after you were done. Now, I want to join the united front to end the most widespread cause of human suffering – aging.

When did you first hear about SENS and what was it that interested you about the concept?

It was a very serendipitous moment that inspired me to read Aubrey de Grey’s book Ending Aging in 2008. I was living in Louisville, Kentucky and spent my free time from working at a White Castle frozen hamburger factory hanging out in a local coffee shop called Heine Brother’s Coffee. Adjacent to that coffee shop was Carmichael’s, a local, independent bookstore. Sitting in a booth in the coffee shop one morning, I was feeling down due to the tough finances of working a blue collar job, lack of sleep from caring for two babies and the misery of war that dominated the news.

Looking down a hallway into the bookstore, a beam of sunlight shone down during a cloudbreak. I left my seat to feel that light on my face to lift my spirits. I must have basked there for nearly a minute. Afterwards, I went straight to my favorite section, Science & Math. And what I found was not just a book, but hope. While Barack Obama was telling us all about hope and change, I was discovering it for myself. Ending Aging spoke to me. Dr. de Grey told us not to accept humanity as the limits of our DNA.

Challenge the status quo and possibly discover how great we may become. Every generation believes that they can do better than their parent’s generation. Until one day that generation wanes into the symptoms of aging. Great men and women lose their dignity because a care worker or family member has to perform what once were remedial tasks for them. Even as their body and mind deteriorates, the younger generation works diligently to absorb their wisdom and love.

This touched me deeply because I loved my parents, grandparents, aunts, uncles, cousins, and other family members and friends. For religious people, you can squelch some of the pain from losing someone to aging with the thought of seeing them again in heaven or some other afterlife concept. As an atheist, I didn’t have that option. The seed of Transhumanism was planted within me and Aubrey de Grey was to blame.

The indecencies attached to the aged bodies of our loved ones wasn’t what sold me on SENS. Dr. de Grey’s analogy of maintaining an antique car caught my attention early in the reading of his book. This was a direct appeal to my inner mechanic. I read during my 30-minute lunch breaks at the White Castle hamburger factory. Separating six burgers into three sets of two on a transfer belt and sliding them into a moving slot to be wrapped in cellophane at a rate of one pair per second, I would let my mind wander into another world.

What are the seven categories of damage that would need to be reversed? Is this list all encompassing? Doing repairs may be easier than changing metabolic pathways, but would it even be possible. What would a society be like if age-related illnesses were eliminated? Aubrey addressed each of these issues and the scientific community slowly started to accept his ideas when they couldn’t disprove them. I was onboard and wanted to be a part of the next step in human improvement.

What did it inspire you to do?

There was this moment where I decided to stop spoon feeding my wife the ideas of SENS and unleashed all my thoughts on her at once. It took place during a long hike where unconsciously I knew she couldn’t escape. She remained quiet and a little scared for hours while I spoke of cellular biology, the ills of aging and my plans to become a doctor or researcher. She held two Master’s degrees. I, on the other hand, was busy retraining National Guardsmen who were heading to Iraq and worked various positions in a frozen food factory along with several low paying manual labor jobs.

I wasn’t naïve to the difficulties of academic life. I did well academically in high school graduating with a 4.0 and winning 1st place in a district academic meet in mathematics. I attended Virginia Tech to become a chemical engineer but wasted my years not focusing on studies. Instead, I focused on failed relationships, peer approval through excessive partying and losing my religion. The final straw came when I had a mental breakdown from financial hardship.

My friend took me to an emergency room because she feared I was going to commit suicide. I hadn’t even told her the moments where I entertained the idea. Living in a rundown apartment without money or food, I took my last breath and submerged myself into the bathwater locking my legs in a manner that would make it difficult to escape. I looked up at the surface of the water and listened for God to speak to me. I heard nothing.

This shocked me because I was committed to the task at hand. In disbelief, I untangled my legs and slowly rose out of the water like an atheist baptism. My perspective of the world was wrong. I was living a lie. I packed up my car with some essentials, left most of my possessions behind and headed back to Eastern Kentucky. While driving home, I had convinced myself that I would never attend college again and I would find a new path to happiness.

I spent the next decade struggling to make ends meet. Various levels of depression oversaw my behaviors. I worked menial jobs, engaged in fist fights, became homeless for a couple of short stints and embraced risk-taking as a way to feel something inside over the numbness of a failed life. By the time I met my wife I was stabilized. I couldn’t tell her all the things I had seen and done out of fear she might wise up and leave this Hillbilly alone. So when I proposed the idea of me becoming a researcher, she was worried that our stable life would enter the chaos of my former life.

It became apparent that working 60+ hours a week at a factory and having two kids under the age of three would not be an ideal time to go back to school. Hence, we waited. I obtained a horizontal promotion as a service technician for the restaurant division. I loved this job. I learned how to braze copper for air conditioning, worked concrete, operated scissor lifts to change out parking light ballasts and repaired deep fryers, grills and milkshake machines. I still read cellular biology books in my spare time and googled Aubrey de Grey more than once a week to see his progress. Then, an opportunity presented itself to me.

My neighbor worked for Kentucky Organ Donor Affiliates (KODA) as a Donor Center Coordinator. He found it interesting that this mechanic neighbor of his was reading biology textbooks when he wasn’t being called out in the middle of the night to fix a freezer. He asked me if I would be interested in a career in the medical field and said he could get me an interview but that was it.

After waiting for three and half years, I had to decide if I should risk it all to pursue my dream. Soon I would not be the only one taking a chance. I had to submit a resume before my interview. There was nothing in my past that would qualify me for this job. I prepared a bare bones resume. My new boss confronted me on the simplicity of my resume. I told him that there was nothing on paper that would qualify me for this job.

He rebutted, “So, why should I hire you?” I explained to him that my qualifications were in my mind and my heart.

He quizzed me on biology, medicine and interpersonal skills. I compared the cardiovascular system to an air conditioner. The heart is the pump. You have a high and low pressure side. The capillaries were like evaporators but instead of absorbing heat they were delivering oxygen and nutrients. He hired me and said they could teach me what I didn’t know. I accepted the lower paying job which worked from 7 PM to 7 AM three days a week and started attending the University of Louisville during the day shortly thereafter.

Wow, so you changed your career completely, how hard was that to do and what were some of the challenges you encountered?

Well, your intuition is correct about the difficulties of switching careers. The transition was tough because I chose to work both jobs for a couple of months to ensure myself that I could do the job. I used all my vacation from White Castle to train during the day at KODA. Once “vacation” ended, I trained on night shift and worked my maintenance job during the day. Also, I was on-call at night every other week for maintenance emergencies.

One night after working non-stop for three days, I couldn’t fall asleep because my heart was pounding and my face and extremities went numb. Like many people, I had mistaken my first anxiety attack as a cardiac event. My wife drove me to the ER where the doctor said that my EKG and blood work were perfect.  He asked, “Are you experiencing any stressful events in your life?” One aspect of my new job “The Approach” took place the night before my anxiety attack.

As a Donor Center Coordinator for KODA, I received call-in death reports from nurses in one of our associated Kentucky, Indiana and West Virginia hospitals. After screening the medical history of the patient, I had to determine eligibility for tissue and eye donation. Potential candidates for donations required consent from the next of kin regardless of registry status. It was a nerve-wrecking event to ask the legal next of kin for consent just minutes after their loved one’s death.

If consent was obtained, then I recorded a 20 to 30-minute medical-social questionnaire, which included invasive questions dealing with health, sex, drug use and jail time. I spent the next five years failing to remedy my anxiety by trying eight different anti-depressants. Yet, the experience of making a difference in people’s lives and working with some of the best coworkers I’ve ever had made it all worth it. With great support from family and friends, I finished two degrees, BS Pure Mathematics and MS Biostatistics.

So what are you doing right now as part of your studies?

Currently, I am focusing on my studies as a first year PhD student in Biostatistics in the beautiful state of Colorado. The teaching staff here is incredible. They are pushing me to be the best I can be while still providing me some space to allow my family and myself to adapt to our new environment. I am taking a course on genomics which has a strong emphasis on the technology of measuring gene expression and various sequencing platforms.

I just published my first paper in Breast Cancer Treatment and Research as a primary author, called “Clinical outcomes linked to expression of gene subsets for protein hormones and their cognate receptors from LCM-procured breast carcinoma cells”. This paper evolved from my Master’s thesis. I will be presenting my work at the San Antonio Breast Cancer Symposium in December. I was honored to be accepted for the 2nd time and a 3rd poster presentation.

Soon I will be collaborating on a methods based paper with my new colleagues at the University of Colorado Denver as part of my research assistantship.

What do you enjoy the most about your work?

I enjoy the science. As a statistician, I have the pleasure of testing real hypotheses. Why is that a pleasure? Because you can hypothesize as many good questions as you want, but unless you have the skill set to quantify those questions, you can’t answer it with any appropriate level of certainty. In addition, it can be challenging. The greatest reward comes from overcoming the greatest feats. With the incredible volumes of omics data challenging scientists, there emerges possibilities for novel discoveries.

Which of the seven areas of SENS interests you the most and why?

I would have to say OncoSENS. My research has been in breast cancer and I’m learning more about epimutations in my genomics class. Also, most of us know someone close that is fighting cancer, survived it or succumbed to it. My mother-in-law starts chemo and radiation this week in her fight against breast cancer. I could overwhelm the rest of this interview with stories of triumph and loss from the disease. I want humanity to learn how to control damage in all the seven areas, but this one I take personally.

What do you think about the shift in aging research towards crowdfunding, for example, the recent OncoSENS and MitoSENS projects on Lifespan.io?

I was delighted to see the progress that the SENS Research Foundation has made in this area. I believe it connects people more intimately with the benchtop research, the scientists and the research community. It can feel good to donate to charity or a cause, but you don’t really know how your donation is being implemented other than generalities. Crowdfunding makes you feel like your Mark Cuban in the Shark Tank trying to discriminate not only what product (research) might work but what product you want to be apart of.

What are your future plans career wise?

Get my doctorate! As my granny always said, “Don’t count your chickens before they hatch.” Given that statement of humility, I would like to work on a research team in a biotech company. I am open to academic research and wouldn’t discount any opportunity. My desire is to spend my days working with innovative people to solve the mysteries of controlling aging. I don’t care what platform provides that for me.

Do you have a take home message for those reading who might want to help but think they have nothing to contribute?

Yes, first I want to thank LEAF for giving me this opportunity to speak to the community. My only purpose here is to inspire someone else to find their way to make a difference. When I started I didn’t know it was going to be entering academia. I certainly didn’t know it would be learning biostatistics, a field unbeknownst to me until I neared the completion of my BS Mathematics degree. Be patient, but also be vigilant to find that connection to the next chapter in your life. I described my history in a very exposing, intimate manner because I couldn’t convey my honesty without those details. It wasn’t easy. I had to fight for it. I had to fail more times than succeed. You may not even know what special skills you possess and can offer until you try something.

Controlling the scourge of aging probably needs funding more than another person with a science degree. If you have the money to give, then let my story be a microcosm of the passion of the researchers working at SENS and its affiliates. If I weren’t a poor 42-year old college student, then I would entrust my money with someone like me. Someone that doesn’t care about status or personal wealth. Someone that feels it is their purpose in life to end the largest contributor to human suffering.

I have always believed Dr. Aubrey de Grey is that person. I also believe that most of the people working for him aren’t his employees. They are his compadres in a war to defeat an enemy that has dominated us since life began. We are the soldiers of compassion. Now, you have to choose your weapon. I’m sure there are some of us that can’t financially contribute, but you can advocate for the cause. I’m doing just that by telling you about my journey.

Feel free to share my story with someone you think it may inspire. Let’s shift the paradigm away from the normality of age-related death.

Conclusion

We would like to thank Mike for taking the time to share his life with us and for his honest and inspiring story. Advocacy is all about the willingness to take action and do something about a situation; we hope Mike’s story has inspired some of you today.