New Year, Same Goal to End Age-Related Diseases| Lifespan Research Institute

Date Posted: January 26, 2023

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New Year, Same Goal to End Age-Related Diseases

The new year is well underway, and we have been our usual busy selves. Join us for the first editorial of the year, and find out about the awesome things we have been doing for longer, healthier lives.

Decentralized science could support aging research progress

Lifespan.io President Keith Comito recently appeared in Cointelegraph, a news site covering fintech, blockchain, bitcoin, and decentralized science (DeSci). In this longevity-related article, Keith highlights the benefits of blockchain tech and decentralization in longevity research.

“We started our nonprofit back in 2014. Back then, few credible researchers would be caught dead saying they were working on aging. It was still kind of a scientific backwater. So, we wanted to emulate what the cancer research advocates did, starting in the ‘40s.” – Keith Comito

Keith is spot on when he talks about how things were just over a decade ago, fortunately things have changed a great deal since our early days. More and more credible (and less “incredible”) researchers have gotten on board with the idea that aging is something that we can and should do something about.

A decade ago, suggesting that aging could be reversed could have ended your career; today, there are an increasing number of researchers involved in serious efforts to develop rejuvenation technologies with the goal of slowing or even reversing aging.

One of the things holding back rapid progress in our field is funding. Traditional funding systems have a tendency to be risk averse, which means the more bold, high-risk, high-reward projects are usually overlooked in favor of safer but less ambitious projects. The good news is that DeSci, blockchain-based systems have great potential for getting around this problem.

We highly recommend checking out this article and finding out why Keith believes that the power of DeSci could be critical in funding aging research in the future.

If you would like to learn more about how DeSci based funding works, check out our topic on that very subject.

Tiffany Vora joins the Lifespan.io Industry Advisory Board

Biologist and science speaker Dr. Tiffany Vora has joined our industry advisory board and will be helping to support our ongoing growth and development this year.

She has a wealth of experience in advising on how best to harness technology for a better future. This includes drawing on her background in molecular biology and biotechnology as well as her science communication skills.

Tiffany is the Faculty and Vice Chair of Medicine and Digital Biology at Singularity University, Faculty at EY Tech University, and also a non-resident Fellow of the GeoTech Center of the Atlantic Council.

I am thrilled to be joining Lifespan.io as an Industry Advisory Board member. It’s a critical moment, with longevity science making important strides as businesses and societies start to grapple with the opportunities – and challenges – of longer, healthier lives. I’m looking forward to supporting the Lifespan.io community in their advocacy, education, funding, and research efforts for longevity.

We look forward to working with Tiffany in the future and benefitting from her expert guidance and knowledge.

Longevity Winter Camp

Lifespan.io Executive Director Stephanie Dainow was a leynote speaker and workshop host for the 2023 Longevity Winter Camp hosted by the Longevity Biotech Fellowship. This retreat-style event featured workshops focusing on the aging and longevity research space as well as discussions with the goal of bringing more talent into the field.

Stephanie was on hand at the winter camp to lead discussion and provide her experience in business development, messaging and communications best practices, and various forms of advocacy critical to not just the longevity field, but also increasing the rate of success when pitching ideas to funders and friends.

Those of us working in the field, especially on the advocacy and journalism side of things, know that communicating with the public can be challenging. There are a lot of misconceptions about our field of research and the goals of life extension, and it can be very demanding dealing with them day in and day out.

Knowing that you are part of a larger community and that you are not advocating for longer healthier lives alone is very motivating. Stephanie was joined at the camp by hosts Anastasiya Giarletta, Omri Amirav-Drory, Matthew Scholz, Matthew O’Connor, Jun Axup, Javier Tordable, Anastasia Egorova, Nikola Markov, Dylan Livingston, Robert Cargill, Mark Hamalainen, Yuri Deigin, Mahdi Moqri, Peter Fedichev, and Alex Kadet.

Events like this allow us to meet with like-minded colleagues and supporters of life extension, which can be a great way to recharge mental batteries. Living in an echo chamber all the time isn’t useful, but connecting with the longevity community at events like these can be a real boost to morale.

Animating the science of aging

Cancer is caused by genomic instability, which leads to mutations in cells that cause them to multiply out of control. It can be considered the poster child of age-related diseases and advancing age is the primary risk factor for developing it. While cancer can affect young people too, the chances of it occurring rise greatly from age 65 onwards.

There are hundreds of known types of cancer, and they originate in many different organs and tissues. We teamed up with SENS Research Foundation to create a Life Noggin video that focuses on the SENS approach to treating cancer.

We have a second helping of video goodness from Blocko, the host of Life Noggin. This time, we teamed up with the folks at NOVOS to produce a video about aging biomarkers, particularly epigenetic clocks. These clocks measure your biological age and give a true picture of how old you really are, not just how many candles are on your birthday cake.

Life Noggin is our edutainment channel that explains science and technology in a fun animated pop-sci style. Because we have an audience of 3.26 million subscribers, we can engage the wider science community about all the amazing research happening right now. This is an example of how we use education and edutainment to engage new audiences about aging and rejuvenation research.

We would like to thank SENS Research Foundation and NOVOS for sponsoring these videos. If you are interested in sponsoring your own video on Life Noggin, please feel free to get in touch with us.

Longevity Hackathon

Lifespan.io President Keith Comito was one of the mentors for the recent VitaDAO Longevity Hackathon.

The event was a longevity-focused hackathon, hosted by VitaDAO, and supported by Lifespan.io, the Healthy Life Extension Society (Heales), the Albert Einstein College of Medicine, R42, the Foresight Institute, and the International Longevity Alliance.

With a prize fund of 5,000 USDC, 10,000 VITA, and 1,000 euros, the hackathon saw 10 teams compete over Friday to Sunday last week.

Keith had this to say about the hackathon:

During the ideation weekend, I offered guidance to the participants and helped to steer their projects towards focusing on targeting the causes of aging. There were around 100 participants competing in the hackathon composed of people with backgrounds in biotechnology or IT. Some of the participants were new to theories like the hallmarks of aging, and it was a great experience helping to prime a new generation of researchers and developers for our field.
By the end of the weekend, the participants had formed 10 teams ready for the Hackathon itself. They focused on various areas of research including sirtuin activating compounds, prevention and treatment of age-related diseases, drug discovery, deep learning in healthcare, and genomics.
At the end of the event, the teams gave their presentations, and myself and the other judges voted to choose the winners. The winners were based on various criteria such as innovation, execution of the concept, presentation, and relevance to the core drivers of aging.

The winners have now been announced, and we wish to give our congratulations to each of the winning teams!

The winning teams have been allocated both cash and VITA tokens to help their projects develop. Among the winners, there is a particular focus on systems with open source and decentralization components. This is further evidence that decentralized science (DeSci) could be a powerful driver of progress in our field in the near future.

Overall, it was an exciting experience to be a part of; and we applaud LongHack and VitaDAO for working to build our community and to bring more researchers, computer scientists, and passionate altruists into our field.

Save the date for Ending Age-Related Diseases 2023

On August 10-12, 2023, we will be holding our sixth annual Ending Age-Related Diseases conference to bring entrepreneurs and investors, pharma and biotech companies, researchers, and government organizations together. Fostering the exchange of information and encouraging cooperation between the various parts of the industry is a large goal for our non-profit organization.

Solving aging will need a coordinated industry working together to turn aging research into prescribable medicine. This is where Lifespan.io is really helping to move things forward and is the focus of our conference. We are currently focusing on tangible outcomes and our next steps.

This will be a mixed virtual and physical hybrid event taking place in New York City and online. We will be announcing speakers, opening ticket sales, and publishing a program in the coming months. If you would like to stay informed about the conference and ticket offers, register for our free newsletter today!

Clubhouse: Why Longevity Research Matters Now

On the Clubhouse social media platform, Keith Comito and Stephanie Dainow took part in a discussion panel along with Chauncey St. John, Maria Entraigues Abramson, Florina Gobel, Ravi Jain, Michael Rae, Lilli Fishman, and Nita Jain.

The panel explored why there should be more focus on aging and longevity research. While our field is making some really great advances in its understanding of aging, it is relatively poorly funded compared to other areas of medical research, such as cancer, stem cells, and tissue engineering.

DeSci: Fad or Future?

Decentralized science (DeSci) is poised to be a catalyst for progress in our field and could present a viable alternative to traditional funding sources. Moonshot projects that fall foul of the risk aversion culture in traditional grant systems could see the light of day via the DeSci approach.

Lifespan.io recently took part in an online discussion panel about DeSci. The topic of the panel was “DeSci: Fad or Future?”. To discuss it, Dinidh O’Brien, Head of Public and International Relations at Data Lake and MC of the roundtable, invited Keith Comito, President of Lifespan.io; Jelani Clarke, part of the core team at DeSci World; Jeffrey Hsia, CEO of Scisets; and Dr. Wojciech Sierocki, Data Lake’s co-founder and CEO.

Support us with the Longevity Cause Fund

The Longevity Cause Fund is a cryptocurrency fundraiser in partnership with SENS Research Foundation and the Methuselah Foundation, facilitated by Angel Protocol.

All proceeds from the fundraiser will go to these three non-profit foundations in support of aging research and advocacy.

This is an endowment scheme designed to create sustainable funding for key players in the aging research and advocacy community. Half will be used for anti-aging work that is currently underway. The rest will be invested in perpetual endowments that will provide ongoing support for this work — forever. Aging affects us all.

Great news: the first $10k donated is also being fund matched by the Angel Alliance. That means any donation no matter how big or small will be worth even more! Help us help you to stay healthier for longer by making a donation today!

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Yes I will donate❤️

Date Posted: January 25, 2023

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Caloric Restriction Does Not Extend Lifespan in Every Model

In a preprint paper, researchers have evaluated the effect of caloric restriction on two long-lived planarian species in various environments that mimic the stochasticity of the real world [1].

Does the theory hold?

According to a theory that is largely based on plentiful data from model organisms, restricted food intake (caloric restriction) extends animals’ lifespans and delays their senescence. However, one shortcoming of these studies is the use of short-lived animals, such as flies and mice. Given that people are long-lived, extensive research on animals with longer lifespans is needed to get a fuller picture of caloric restriction and its effects.

There are also still many unanswered questions relating to optimal duration, the quality and composition of food, and when to begin caloric restriction. Another caveat is the constant feeding regime that is normally implemented in calorie restriction studies.

In order to get insights into these questions, the researchers conducted a series of experiments on two planarian species, Schmidtea mediterranea and Dugesia tahitiensis. They varied the quantity, quality, and frequency of food availability to see their effects on the population size, reproduction, and longevity of the animals.

Planarians are quite different from people, to say the least: they have the ability to change size depending on the availability of resources, and their regenerative abilities are like those of some starfish and earthworms, able to form whole organisms from severed parts. Nevertheless, this research design is invaluable to understand the effect of caloric restriction in realistic conditions.

Modeling the complexity of the real world

Three cultures of 10 asexual planarians of each species were initially used. The researchers then increased the overall sample size by cutting each individual twice, thus getting three individuals of the same age. At this stage, the animals were fed ad libitum followed by a starvation period.

Next, a full factorial experiment was conducted on 600 planarians of each species. This means that the researchers combined and varied several diet factors for each experimental group of 10 individuals: two levels of carbohydrate composition, three levels of food amount, and two levels of feeding frequency.

First, the researchers hypothesised that with more food available, whether amount-wise or frequency-wise, the survival of planarians would decrease. However, their experimental data did not show any difference in survival across various treatments for either species.

Second, the scientists analyzed the effect of the treatments on body size. They show that for S.mediterranea, most treatments led to a change in the population composition, with a higher number of small planarians and fewer large individuals. For D.tahitiensis, the same was observed only in planarians that were frequently fed.

Finally, the experiment did not show that the planarians’ population size was clearly dependent on food availability. In the case of S.mediterranea, most treatments resulted in population decline, while the D.tahitiensis population either remained stable or increased.

Therefore, the researchers have come to the conclusion that when multiple factors interact with reduced caloric intake, there is no beneficial effect of the latter on the survival of planarians. The outcome of reducing caloric intake in these species is thus very much dependent on the frequency, quality, and quantity of food. The optimal regime, if any, is still in question.

Abstract excerpts

CR studies are largely implemented in unrealistic environments that do not consider how interacting, stochastic drivers impact longevity. Indeed, little is known about the impact of stochastic resource availability on senescence, even though environmental stochasticity is the norm rather than an exception in natural populations. Here, we examine whether and how stochasticity in the quantity, quality, and frequency of resources impact lifespan, life history trait trade-offs, and population structure in two long-lived planaria: Schmidtea mediterranea and Dugesia tahitiensis.
As before, no clear pattern emerges in the changes in population counts under CR conditions for both species. As such, we did not find evidence of CR providing benefits in terms of lifespan nor trade-off between population counts, survival, and body size. We call for the careful reevaluation of decades of CR work in short-lived species, by expanding and testing predictions in more realistic settings and across a wider range of life histories.

Conclusion

This study calls into question the widely accepted caloric restriction theory, especially when applied to long-lived animals under realistic conditions. Although it is difficult, if not reckless, to make conclusions about the lack of caloric restriction benefits for humans based on the results obtained in planarians, we are once again reminded that more research is needed to find out what really works as a lifespan-extending approach.

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Literature

[1] Deere, J. A., Holland, P., Aboobaker, A. & Salguero-Gómez, R. Calorie restriction brings no benefits to lifespan under stochastic environments. bioRxiv 2023.01.12.523873 (2023) doi:10.1101/2023.01.12.523873

The Journal Club is a monthly livestream hosted by Dr. Oliver Medvedik which covers the latest aging research papers.

Date Posted: January 25, 2023

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Partial Reprogramming Extends Lifespan in Old Mice

The journal club returns on Tuesday 31st January at 12:00 Eastern on our Facebook page with host Dr. Oliver Medvedik. We are looking at a preprint this time where partial reprogramming factors were used to reverse some aspects of aging in old mice. The paper is called Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice.

You may also be interested in reading our article Gene Therapy to Induce Epigenetic Reprogramming, which covers this publication.

Abstract
Aging is a complex process best characterized as the chronic dysregulation of cellular processes leading to deteriorated tissue and organ function. While aging cannot currently be prevented, its impact on lifespan and healthspan in the elderly can potentially be minimized by interventions that aim to return these cellular processes to optimal function. Recent studies have demonstrated that partial reprogramming using the Yamanaka factors (or a subset; OCT4, SOX2, and KLF4; OSK) can reverse age-related changes in vitro and in vivo. However, it is still unknown whether the Yamanaka factors (or a subset) are capable of extending the lifespan of aged wild type mice. Here, we show that systemically delivered AAVs, encoding an inducible OSK system, in 124-week-old mice extends the median remaining lifespan by 109% over wild-type controls and enhances several health parameters. Importantly, we observed a significant improvement in frailty scores indicating that we were able to improve the healthspan along with increasing the lifespan. Furthermore, in human keratinocytes expressing exogenous OSK, we observed significant epigenetic markers of age-reversal, suggesting a potential reregulation of genetic networks to a younger, potentially healthier state. Together, these results may have important implications for the development of partial reprogramming interventions to reverse age-associated diseases in the elderly.

Date Posted: January 25, 2023

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Journal Club January 2023

Abstract
Aging is a complex process best characterized as the chronic dysregulation of cellular processes leading to deteriorated tissue and organ function. While aging cannot currently be prevented, its impact on lifespan and healthspan in the elderly can potentially be minimized by interventions that aim to return these cellular processes to optimal function. Recent studies have demonstrated that partial reprogramming using the Yamanaka factors (or a subset; OCT4, SOX2, and KLF4; OSK) can reverse age-related changes in vitro and in vivo. However, it is still unknown whether the Yamanaka factors (or a subset) are capable of extending the lifespan of aged wild type mice. Here, we show that systemically delivered AAVs, encoding an inducible OSK system, in 124-week-old mice extends the median remaining lifespan by 109% over wild-type controls and enhances several health parameters. Importantly, we observed a significant improvement in frailty scores indicating that we were able to improve the healthspan along with increasing the lifespan. Furthermore, in human keratinocytes expressing exogenous OSK, we observed significant epigenetic markers of age-reversal, suggesting a potential reregulation of genetic networks to a younger, potentially healthier state. Together, these results may have important implications for the development of partial reprogramming interventions to reverse age-associated diseases in the elderly.

As a Lifespan Hero, you can join us live for the call using the details below:

https://lifespan-io.zoom.us/j/84196064528?pwd=dFptbmg2SStKdXlsNnRGb080RW45UT09

Meeting ID: 841 9606 4528

Passcode: 172040

Date Posted: January 24, 2023

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Longevity Investors Lunch at Davos

A Longevity Investors Lunch hosted by Maximon, Longevity Investors Conference, and Biolytica has been hosted at a satellite event of the well-known Davos conference. The press release is included here.

Longevity stays in the limelight on the streets of Davos for the second time during this year’s World Economic Forum (WEF). The world is growing – and aging – at a rapid rate, and nearly a third of the world’s population will be over 60 years old by 2050.

So, how do we prepare to age healthy and live a long happy life?

The “Longevity Investors Lunch”, a satellite event focusing on longevity and rejuvenation during the World Economic Forum, was organized on January 18th and discussed the latest technologies and research among prominent scientists, academia, entrepreneurs and investors. The event was co-organized by Maximon, Longevity Investors Conference and Biolytica and it was a prelude to the “Longevity Investors Conference”, happening later this year, on September 27-29, 2023, at Le Grand Bellevue Hotel in Gstaad, Switzerland.

Over 50 high level investors and key opinion leaders gathered together and showed how far the longevity industry has come. The focus of the event was on change and transformation of global health, innovative technologies and many more.

The two panels, moderated by Sabinije von Gaffke (Head of Sustainability, Nibiru Software) covered Longevity as the mega trend where the latest discoveries in research were discussed as well as shed light on the longevity investment landscape. The discussions on stage featured renowned experts and prominent longevity venture builders such as Prof. Dr. Björn Schumacher (Professor and Director, Institute for Genome Stability in Ageing and Disease, University of Cologne), Dr. Brian Kennedy (Director, Centre for Healthy Longevity and Professor Departments of Biochemistry and Physiology at National University of Singapore), Dr. Dina Radenkovic (Co-founder & CEO of Gameto & Partner, SALT), Collin Ewald (Assistant Professor, ETH Zurich and Founder of Swiss Society for Aging Research), Jörg Rieker (Founding Partner, Maximon), Dr. Kemal Tunc Tiryaki (Founder, MAGE Group), Christian Schmid (Head Asset Management, Kaleido Privatbank).

Biolytica’s CEO Dr. Rob Konrad Maciejewski gave a talk on “Using the power of data to change healthcare and optimize longevity”, where he gave an opportunity to the guests of the event to get some insight into Biolytica’s new health data platform. Biolytica NEXUS is a tool for healthcare professionals such as longevity clinics, centers for preventive medicine, longevity physicians and others that uses AI and advanced analytics to combine genomics, epigenetics, biomarkers, wearable device data, lifestyle information such as nutrition and many others to create hyper personalized health and longevity journeys for patients.

The hosts of the event, Dr. Tobias Reichmuth (Co-Founder, Maximon & Longevity Investors Conference), Marc P. Bernegger (Co-Founder, Maximon & Longevity Investors Conference) and Dr. Rob Konrad Maciejewski (Co-Founder & CEO, Biolytica) opened the event while giving an overview of the longevity industry and closed it explaining why company building in longevity is needed now.

“We are very proud to be one of the first ones to bring the important topic of longevity to Davos. We are already looking forward to the Longevity Investors Conference, where we will have the opportunity to continue the important conversations we started in Davos and involve more longevity leaders on stage who will talk about important developments in the longevity industry as well as investment opportunities in the field.”, says Marc P. Bernegger, Founding Partner at Maximon and the organizer of the Longevity Investors Conference in Gstaad.

Dr. Rob Konrad Maciejewski adds, “A common misconception about longevity is that it’s only about adding more years to the clock of life. And a lot of people rightfully ask: ‘Why would I even want to spend more miserable years at old age?` But the concept of longevity is different and goes far beyond that. The current healthcare systems around the globe are, in essence, sick-care systems – we wait for people to become ill, and then spend billions of dollars to manage chronic diseases with medications – at greatly reduced quality of life. This is not sustainable, and not ethical. Longevity is not about just “adding years” – it’s mainly about developing strategies to keep people healthier for as long as possible, to extend the time we can spend in great health, to greatly improve their quality of life as they age – and if we can then add a few more healthy years, that’s a bonus. We believe the key to this is to better understand the human body, and the key to that is data, which is what Biolytica is focusing on.”

The “Longevity Investors Conference” is the most exclusive conference for longevity investors. It provides relevant insights into the longevity subject, expert education, investment opportunities, and excellent networking opportunities in an exclusive location.

The motivation to organize the “Longevity Investors Conference”, said Dr. Tobias Reichmuth, Founding Partner and organizer, is clear: “The longevity industry is highly attractive for investors. We state a lack of education and information for investors and want to change this. While there are scientific-oriented conferences, a professional and global investor focused longevity conference was missing so far.”

Longevity now ranks as one of the most significant forces shaping the global economy, opening up multi-trillion dollar opportunities to reshape societies, hopefully for the better. It has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes. It will be one of the largest, if not the largest investment opportunity in the decades to come.

For more information and details please visit www.longevityinvestors.ch

info@longevityinvestors.ch

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Date Posted: January 24, 2023

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NMN Reduces Metastasis in Difficult Breast Cancer Model

In a new paper published in Nature, scientists have found that raising NAD+ levels via supplementation with nicotinamide mononucleotide (NMN) activates SIRT1 to dampen metastasis in mouse TNBC models [1].

A double-edged sword

NAD+ is a ubiquitous co-enzyme that facilitates numerous processes in our body, from energy production to DNA repair. Its levels decline with age, and its supplementation via precursors (usually NMN or NR) has shown multiple health benefits in animal models and humans.

Nicotinamide Adenine Dinucleotide (NAD): Benefits and Research

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.
Read More

However, like many biomolecules, NAD+ is a double-edged sword, including its self-contradictory relationship with cancer. On one hand, NAD+ is used as fuel by many types of cancer cells [2]. On the other hand, it boosts anti-cancer immune response. NAD-dependent enzymes such as sirtuins and PARP also seem to have a context-dependent effect on cancer [3].

Here, the researchers studied the effects of NAD+ on triple-negative breast cancer (TNBC). TNBC cells lack the three common receptors that are usually found on the surfaces of breast cancer cells, which limits therapeutic options.

NMN slows migration and invasion

First, the researchers generated primary tumors by injecting HCC1937 cancer cells, a common model of TNBC, into the mammary fat pads of immunocompromised mice. Continuous treatment with NMN significantly impeded tumor growth and metastasis. Similar results were obtained using actual TNBC cells taken from a cancer patient.

The researchers then proceeded to study NAD+ metabolism in vitro and found that NMN supplementation rapidly increased intracellular NAD+ levels. While the treatment did not affect the proliferation of cancer cells, it slowed their migration and invasion.

RNA sequencing of tumor samples revealed that NMN supplementation led to the activation of genes involved in longevity-regulating pathways and glutathione metabolism. Glutathione is probably the most important antioxidant that humans produce [4].

The role of SIRT1 activation

Recent studies have shown that some protective effects of NAD+ might be attributed to its regulation of SIRT1, a member of the sirtuin family. The researchers conducted analysis of several existing large datasets and found that TNBC was associated with lower SIRT1 levels, and the mRNA expression of SIRT1 was negatively correlated with the severity of breast cancer. Using this data, the researchers also showed that breast cancer patients with higher sirtuin levels had longer overall survival and better relapse-free survival rates. SIRT1 levels were also lower in high-metastatic versus low-metastatic TNBC cells.

The invasion potential of TNBC cells was significantly decreased by two different SIRT1 activators, including resveratrol, a molecule popularized by David Sinclair’s research. In this study, resveratrol proved to be a more potent downregulator of TNBC cell invasion than the second molecule, CAY10602. However, both compounds failed to affect TNBC cell proliferation rate. SIRT1 inhibition had the opposite effect on migration and invasion.

Next, the researchers genetically engineered TNBC cells to stably express SIRT1. Compared to regular TNBC cells with impaired SIRT1 production, the in vivo models based on SIRT1-expressing cells produced significantly less lung metastases. Similar results were achieved with NAD+ supplementation. However, this effect was abrogated by SIRT1 knockout.

Mediation of antioxidative activity

Since NAD+ treatment upregulated genes involved in glutathione metabolism, the researchers turned their attention to oxidative stress. The production of reactive oxygen species (ROS), which cause oxidative stress, was decreased both by NMN treatment and by SIRT1 overexpression. Those effects were recapitulated to some point by the ROS scavenger NAC. Interestingly, previous research suggests that ROS promote metastasis in cancer [5].

The researchers then discovered a downstream target of SIRT1 that might be responsible for its anti-cancer effect. The protein p66Shc is known to promote ROS production when it is phosphorylated, but SIRT1 can block its phosphorylation. When p66Shc phosphorylation was blocked by other means, the results resembled those of NMN supplementation and SIRT1 overexpression.

Conclusion

NAD+ and SIRT1 have ambiguous, context-dependent relationships with cancer. This study suggests that specifically in the context of triple-negative breast cancer, raising NAD+ levels by NMN supplementation activates the SIRT1-mediated antioxidative response, which might prove useful in treating this stubborn subtype of breast cancer.

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Literature

[1] Jiang, Y., Luo, Z., Gong, Y. et al. NAD+ supplementation limits triple-negative breast cancer metastasis via SIRT1-P66Shc signaling. Oncogene (2023).

[2] Yaku, K., Okabe, K., Hikosaka, K., & Nakagawa, T. (2018). NAD metabolism in cancer therapeutics. Frontiers in oncology, 8, 622.

[3] Cantó, C., Menzies, K. J., & Auwerx, J. (2015). NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell metabolism, 22(1), 31-53.

[4] Kerksick, C., & Willoughby, D. (2005). The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. Journal of the international society of sports nutrition, 2(2), 38.

[5] Porporato, P. E., Payen, V. L., Pérez-Escuredo, J., De Saedeleer, C. J., Danhier, P., Copetti, T., … & Sonveaux, P. (2014). A mitochondrial switch promotes tumor metastasis. Cell reports, 8(3), 754-766.

Date Posted: January 24, 2023

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Open Longevity Foundation Announces Open Genes Database

Open Longevity Foundation has announced Open Genes, a database of longevity-associated genes and a tool for future anti-aging therapy development. The full press release is included here.

Open Longevity Foundation released a novel database of genes involved in human aging and longevity — Open Genes. It includes information of more than 2,400 genes, which is the most extensive mapping of human genetics of aging to date. Open Genes provides comprehensive analysis of all human genes involved in major aging processes, contribution into life expectancy and genetic interventions, which affect lifespan of model animals. Open Genes is designed for a wide range of people interested in aging biology, and provides a potent tool for scientists working on the problems of aging and life extension.

The Open Genes database is created to provide the most comprehensive information on genes involved in aging processes, as well as to enhance and simplify the search for potential aging therapy targets. The database includes a detailed description for genes: lifespan-extending interventions, aging-related changes, longevity associations, connections to diseases and hallmarks of aging, gene evolution and functions of gene products. It aims to combine all available data on the genetics of aging and provide convenient tools for searching, assorting, and comparing genes. It describes 2,402 age-related genes, from 1,700 unique research articles; more than 2,000 genetic interventions, affecting lifespan of model animals, 4,648 records of age-related changes in gene activity, 1,458 records on longevity associations with gene variants. Data on each gene associated with aging is much more diverse and detailed than in existing databases (GeneAge, Digital Ageing Atlas, LongevityMap).

Open Genes is created by aging biologists and anti-aging enthusiasts from Open Longevity Foundation (CA, USA), under the direction of Ekaterina Rafikova, Constantine Rafikov and Mikhail Batin. Open Longevity Foundation promotes aging research and life extension ideas, as well as organizes and conducts its own experiments in the field of aging and longevity. The Foundation is based on the principles of open science, where the results of the research should be transparent and available to everyone. The development of Open Genes is a step towards achieving this goal, being an open-source database, open and free for the users.

Open Genes establishes the relationship between the genes in the database and biological processes, which dysregulations characterize human aging. The genes are attributed to the main aging mechanisms revealed to date (so called “hallmarks of aging”), such as genomic instability (e.g., accumulation of damages), cellular senescence, attrition of telomeres, stem cell exhaustion, and altered intercellular communication. Open Genes also summarizes the existing knowledge on genetic manipulations, extending the life of model animals: >9 times in nematodes, >3 times in flies, and >1.5 times in mice. Open Genes provides a structured and detailed description for each experiment (up to 40 parameters), which allows one to more accurately interpret the results of the study. In order to decide which genes need to be added to the database, 6 types of studies and 12 criteria were used. Genes were classified according to the confidence level of the link between the gene and aging. All genes were divided into five confidence levels: highest, high, moderate, low and lowest.

Open Genes database aims to assist in the selection of the most confirmed targets for anti-aging therapy and the search for new ones. The Open Genes team has already identified 25 genes that extended life in mammals and at the same time showed an association with longevity in humans were given the highest level of confidence. The ultimate goal of the project is to create a system of constantly updated databases on aging biology and aging therapy methods with the most qualitative and organized data. These data will be convenient to use in meta-analyses, in search of new targets for aging therapy, in search of potentially successful combinations of genetic interventions, and for experimental design.

Yes I will donate❤️

Date Posted: January 23, 2023

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Allogeneic CAR-T Cells Complete Phase 1 Trial

The results of a Phase 1 clinical trial of allogeneic CAR T cell therapy against multiple myeloma have been published today in Nature Medicine, and they appear to be promising.

B cells, engineered T cells, and lymphodepletion

Multiple myeloma is a cancer of the plasma B cells, which are formed in the blood marrow and are normally responsible for expressing antibodies against pathogens, such as bacteria and viruses. The participants in this study have either a recurrent form of this disease or a form that has not responded to any established treatments.

Cancerous plasma cells express the BCMA protein, which can be used as a target for genetically engineered CAR T cells. However, while engineering the patient’s own cells to target this protein would be ideal and has been shown to work in early clinical trials [1], the researchers hold that it can take too much “vein-to-vein” time; by the time that the full process is complete and the modified cells are ready for injection, the cancer may have significantly, even fatally, progressed.

Therefore, the researchers have developed ALLO-715, pre-existing CAR T cells that can be immediately administered. These allogeneic cells are modified in three main ways: to attack BCMA-producing cells, to knock out the T cell receptor alpha constant that would encourage these T cells to attack unfamiliar cells (such as the patient’s), and to knock out CD52, a differentiation cluster that would normally be a trigger for immunorejection.

In this trial, the researchers also employed ALLO-647, an antibody that removes CD52-expressing cells and causes lymphodepletion. While this is, in essence, attacking the patient’s own immune system (which is already suffering from cancerous B cells), it facilitates the growth and expansion of ALLO-715 cells.

Infection but effectiveness

Given the lymphodepletion regimen, it is no surprise that infection was a serious risk. Most patients were shown to have significant depletion of the immune cells known as neutrophils, and diminished numbers of other immune cells were also reported as adverse events. Cytomegalovirus resurgence was a problem, and pneumonia, blood sepsis, and cytokine release syndrome were shown to occur as well. Some neurotoxic proteins were also found in some patients.

While those adverse events are certainly significant, the researchers found that the treatment is still significantly better than the disease. Multiple myeloma is often fatal, particularly for patients with recurring or unresponsive forms of it. Of the 43 patients (average age of 64) that were treated, 24 received at least 320 million cells along with ALLO-647 and two additional lymphodepletion drugs. The researchers found this to be the optimal dosage regimen, as of this subgroup, six people had moderate partial responses, eleven had very good partial responses, and six had complete responses: their cancer had gone into full remission.

Conclusion

While the results are certainly at least somewhat positive, this therapy is still early in the development process; this was a Phase 1 safety and dosage study that was not placebo controlled. There was a wide variety of responses or lack thereof, and there are as of yet few insights into why it works so well for some patients and not at all for others. This was a somewhat dangerous treatment for an even more dangerous disease; over the course of this year-long study, a total of seven people died of cancer progression and three died of infection. It must be noted here that the mortality risk of aging is even higher.

Still, this represents a milestone in the development of allogeneic cellular therapies. It is easy to see ways in which the effort spent in developing safe and reliable T cell therapies might also be relevant to other diseases in which fresh, compatible cells from an off-the-shelf source would be ideal. If the dangers of immunorejection can be overcome and depleting the immune system can be rendered unnecessary, it may be possible to not only fight cancers with this approach but to combat the aging hallmark of stem cell exhaustion.

Yes I will donate❤️

Literature

[1] Benjamin, R., Graham, C., Yallop, D., Jozwik, A., Mirci-Danicar, O. C., Lucchini, G., … & Daguenel-Nguyen, A. (2020). Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. The Lancet, 396(10266), 1885-1894.

Date Posted: January 20, 2023

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Senescent Cells Leave Fragments Attached to Other Cells

In a preprint paper, scientists have reported that senescent cells transiently adhere to neighboring cells, and, upon departure, leave in place large membrane-enclosed fragments of themselves [1].

Mysterious fragments

Cellular senescence is central to aging, but there are still a lot of unknowns around this complex and heterogeneous phenomenon. For instance, we know that senescent cells are highly “communicative”: they can influence their environment, inducing senescence in neighboring cells [2] and eliciting immune response [3]. They do this via the senescence-associated secretory phenotype (SASP), a diverse mix of molecules such as pro-inflammatory cytokines and chemokines. However, this might not be the only signaling mechanism at their disposal.

Cellular Senescence is one of the proposed reasons we age.

Why We Age: Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
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The researchers started by studying human primary fibroblasts rendered senescent by irradiation. To observe the progression of senescence in single cells, they created a model in which cells marked by the fluorescent protein GFP were mixed at a ratio of 1:1000 with other, non-fluorescent cells. In one group, the fluorescent cells were senescent, but others were healthy and proliferating. In the second group, it was the other way around. In the third group, all cells were senescent, and, finally, the control group contained only healthy cells.

To the scientists’ amazement, after a few days, in addition to GFP-positive cells, smaller GFP-positive spots began to appear. When the researchers imaged them using higher-resolution equipment, those turned out to be not cellular debris but cellular fragments attached to the membranes of adjacent cells. This did not happen in the control group, where both GFP-positive and GFP-negative cells were non-senescent, which ruled out the possibility that the strange effect was caused by GFP.

Origin: senescent cells

To determine the origin of the fragments, the researchers turned to time-lapse imaging, which showed that both senescent and non-senescent cells moved around and routinely made contact with their neighbors.

Contacts between non-senescent cells were brief and ended without damaging either cell. However, when at least one of the cells was senescent, the contacts were sometimes more persistent and resulted in the cells being glued together. As the cells finally moved apart, their bodies stretched until the senescent cell was torn, leaving a part of itself attached to the other cell. Interestingly, the membranes on both the cells and the fragments they left behind quickly sealed, showing effective membrane repair.

Those fragments began appearing in the culture at around day 3 after the induction of senescence, and by day 4, an average of 10-12 fragments per each senescent cell were observed. The fragments were quite large, 7-8 micrometers across, and contained many types of organelles, including mitochondria, ribosomes, and autophagosomes. However, no nuclear matter was found in any of the fragments. In some instances, the researchers also observed adherens junctions: large protein complexes that tie cells together.

When isolated, those senescent cell adhesion fragments (SCAFs) exhibited “spinning, projecting and retracting arms, or crawling-like behavior”. Most of them disintegrated by day 3, creating extracellular debris, although a small part of SCAF contents ended up inside the surrounding cells.

To make sure that SCAFs are not exclusive to irradiated senescent fibroblasts, the researchers experimented with several other combinations of senescence triggers and cell types, such as oncogene-induced senescence in primary fibroblasts and chemotherapy-induced senescence in human liver cancer cells. They also showed that SCAF formation occurs in vivo in mice.

Associations with inflammation and cancer

The researchers analyzed the protein content of SCAFs and discovered associations with damage signaling, immune cell recruitment and activation, inflammation, and neurodegenerative disease.

The researchers also wanted to see what effects SCAFs have on the cells that they end up piled upon. DEG (differentially expressed genes) analysis of those cells produced many correlations with SCAFs, pointing at pathways associated with cell proliferation, migration, and invasion as well as wound healing, cell adhesion, and cancer.

When exposed to SCAFs isolated from senescent cells, healthy fibroblasts showed a significant increase in proliferation and migration velocity. Due to a strong association with cancer signaling, the researchers also investigated the effects of SCAFs on cancer cells. Adding SCAFs to liver cancer cells increased their proliferation. In 3D culture, SCAF-treated cancer cells became more active, invading the gel and forming branches.

This supports the theory that cellular senescence is a double-edged sword that facilitates organismal development, wound healing, and probably cancer resistance, but later in life, it turns from transient to permanent, driving inflammation and, somewhat paradoxically, cancer [4].

Conclusion

This study points to a previously unknown quality of senescent cells that might contribute to our understanding of cellular senescence and its complex relationship with cancer. Given that several different types of senescent cells had exhibited this phenomenon, the researchers also suggest that it might be used as a senescence marker.

Yes I will donate❤️

Literature

[1] Durik, M., Goncalves, D. S., Spiegelhalter, C., Messaddeq, N., & Keyes, B. (2023). Senescent cells deposit intracellular contents through adhesion-dependent fragmentation. bioRxiv.

[2] Nelson, G., Wordsworth, J., Wang, C., Jurk, D., Lawless, C., Martin‐Ruiz, C., & von Zglinicki, T. (2012). A senescent cell bystander effect: Senescence‐induced senescence. Aging cell, 11(2), 345-349.

[3] Marin, I., Boix, O., Garcia-Garijo, A., Sirois, I., Caballe, A., Zarzuela, E., … & Serrano, M. (2022). Cellular senescence is immunogenic and promotes anti-tumor immunity. Cancer Discovery, CD-22.

[4] Giaimo, S., & d’Adda di Fagagna, F. (2012). Is cellular senescence an example of antagonistic pleiotropy?. Aging cell, 11(3), 378-383.

Date Posted: January 20, 2023

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Exploring the Biological Aging Advice in “Younger You”

Dr. Kara Fitzgerald’s new book provides an evidence-based approach to diet and lifestyle that aims to reduce your biological age.

Beginning with epigenetics

Younger You offers a pragmatic and easily understood primer on the role of epigenetics and aging along with an exquisitely detailed plan for how to reduce your biological age. This book is based on refreshingly solid science: the results of an eight-week randomized clinical trial, overseen by Dr. Fitzgerald, that was published in the peer-reviewed journal Aging in April 2021. Participants experienced an average reduction in biological age of 3.23 years over the course of eight weeks as determined using DNAmAge, an epigenetic clock developed by Dr. Steve Horvath of UCLA.

Dr. Fitzgerald has divided Younger You into three parts. Part 1 starts with a basic, foundational explanation of epigenetic change as it relates to chronological and biological aging. She then stresses the need to understand that we can influence how and when these changes occur through scientifically validated lifestyle interventions.

The latter half of this part highlights a case study that illustrates the strategic use of methyl donors, DNA adaptogens, and lifestyle changes: the three pillars of Dr. Fitzgerald’s approach to slowing the advancement of biological age. The first part winds down with a brief history of nutrient-based medicine and a cautionary tale that points to the hazards of isolated nutrient supplementation in favor of a whole foods-based approach to diet. Lastly, Dr. Fitzgerald argues the advantages of the Younger You diet over other longevity-based dietary approaches, such as intermittent fasting and the Mediterranean diet.

A plan to reverse biological age

The second part gets down to the brass tacks of Fitzgerald’s program to reverse biological age. The first chapter opens with a series of assessments, including a Biological Age Self-Assessment (BASA), a Medical Symptoms Questionnaire, and a brief guide to assessing blood work for clues to biological age. These assays provide enough baseline information metrics to gauge progress over eight weeks of using the Younger You diet and lifestyle approach. Next, Dr. Fitzgerald introduces the Younger You Intensive Program. This is the program that the study participants followed.

This eating plan is rich in methyl donors and DNA adaptogens. The mainstay of the diet is dark leafy greens, cruciferous vegetables, and a rainbow of antioxidant-rich vegetables. The bulk of calories come from nuts, seeds, and high-quality oils with modest amounts of high-quality organic animal proteins. Putting these components together yields a keto-leaning diet that is high in fiber and low in sugar.

It consists of roughly 45-50% fat, 15-20% protein, and 30-35% carbs. The amount of protein is 0.66 grams per kilogram of body weight for individuals under 60 years of age; For older individuals 1-1.2 grams per kilogram are prescribed. Organic is encouraged but not mandated, lentils and dairy are largely absent due to their inflammatory potential, and a 12-hour eating window is implemented to capture the benefits of intermittent fasting. In addition to specific guidelines and tables for making food selections, specific menus are also provided for a more scripted approach. Dr. Fitzgerald also provides specific guidelines for vegans and vegetarians.

Dr. Fitzgerald also provides guidance for tweaking the Younger You diet. Technically, the diet already meets the requirements of a paleo diet, and with minor modifications it can be layered into a number of other popular diets.

The Everyday Eating Plan

Following the introduction and details of the Intensive Younger You Diet, an Everyday Eating Plan is also presented. This plan is designed for people who don’t necessarily need the intensive plan and would prefer more flexibility in their daily food choices.

Dr. Fitzgerald also addresses other lifestyle factors including exercise, stress management, and sleep. Program participants are strongly encouraged to engage in enjoyable physical activities at least five days a week that lead to 60-80% of perceived maximum exertion. The importance of stress management is discussed, and engaging in techniques for managing stress, such as meditation, twice a week is recommended. Dr. Fitzgerald also covers the basics of sleep hygiene. Chapter 8 covers supplement support for regular program participants as well as vegetarians and vegans.

Putting the “You” in Younger You

Part three addresses customization for different life stages, including pregnancy and menopause, along with concerns related to genetic testing before moving on to recipes. About 100 pages of recipes are included in addition to several useful appendices, including shopping lists, ingredient notes, nutrient references, a primer on the methylation cycle, and a list of additional resources to round things out.

Yes I will donate❤️

Date Posted: January 20, 2023

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Introducing A Longevity Hackathon for Accelerating Research

The latest hackathon event, LongHack, hosted by the VitaDAO team beginning today and continuing over the weekend, will focus on discovering new approaches to longevity science and inspiring new initiatives in the field.

What is LongHack?

LongHack is a longevity-focused hackathon that is hosted by VitaDAO and supported by Lifespan.io, the Healthy Life Extension Society (Heales), Einstein Albert Einstein College of Medicine, R42, the Foresight Institute, and the International Longevity Alliance.

Offering a prize fund of 5,000 USDC, 10,000 VITA, and 1,000 euros, the hackathon’s ideation weekend helped form 10 teams of dedicated participants who are competing in this current event.

The proposed projects include a drug discovery pipeline that’s able to predict drug efficacy and toxicity more accurately, an atherosclerosis risk estimator app, and nanomedicine for the delivery of sirtuin-activating compounds. We will report more about the projects in the coming weeks once the winners are announced.

What is a hackathon and how does it work?

Hackathons are fast-paced events in which participants gather together to form teams and solve specific challenges over 24 or 48 hours. Also known as hackfests, codefests, and datathons, hackathons have gained popularity in recent years as an agile method of figuring out solutions quickly.

The term “hackathon” (hack + marathon) dates back to a 1999 event held in Calgary, Canada. Although the event can be considered more of a sprint, the name reflects the endurance that the teams exhibit. Here, ‘hack’ is used to cover any type of computer programming.

Often, hackathons are not just interest-based events; participants and winning teams often compete to win prizes or investments into their designed solutions, providing more motivation for those taking part. Such events can be themed; there have previously been fintech hackathons, biotech hackathons, and hackathons focused on startups. By using the principles of agile software development, which prioritize individual contribution and interactions, operational software, collaboration, and responding to change (mentor feedback), hackathons are geared towards productivity.

Traditionally, hackathons were held in a specific location, with participants gathering together for the entirety of the intense work period. However, following the COVID-19 pandemic, some organizers have switched to remote-first models that allow participation from candidates from all over the world.

What should participants expect from a hackathon?

While the environment is fast-paced, participants often enjoy the challenge. The general structure of a hackathon usually includes an introduction from the host, which outlines the aims, objectives, terms, and other details of the event, then a team- or match-making activity, followed by idea sessions, project work, result presentations, and awards. By the end of the event, it is hoped that the teams will be able to present their works-in-progress or minimum viable products to the rest of the group.

World’s most famous hackathons

Since the term hackathon was invented, countless events have taken place all over the world. Perhaps the most famous was the Salesforce-run Dreamforce event, which boasted a massive prize of $1 million for the winners. However, there have been a number of outstanding results from other events, including:

HackMIT: organized by the Massachusetts Institute of Technology and sponsored by top names in tech, such as Google, Facebook, and IBM, HackMIT brings together students from around the world to work on software/hardware projects. By choosing one of its established tracks (education, new frontiers, entertainment, or sustainability), teams compete to win one of the event’s prizes.

Disrupt: hosted by TechCrunch, while not described as a hackathon, Disrupt is a three-day event focused on connecting startups and investors. Selected teams compete on the Startup Battlefield 200, where the top winners will then pitch their companies on the main Disrupt stage for the chance to win the Disrupt Cup and a $100,000 prize.

NASA Space Apps Challenge: founded by the National Aeronautics and Space Administration (NASA) and sponsored by 11 partner agencies from all around the world, participants in this annual 48-hour event take on challenges that are related to that year’s theme. In 2022, ten winners were selected from over 5,300 participating teams.

Summary

Hackathons are fast-paced events, usually held over 2-3 days, where participants form teams and solve problems, generally using coding and an agile development approach. Today and this weekend, VitaDAO is hosting LongHack, a longevity-dedicated event set to accelerate and inspire longevity science projects.

Yes I will donate❤️

Date Posted: January 19, 2023

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The APOE4 Gene Is Associated With Worse Stroke Outcomes

Researchers publishing in Aging have found that there is a correlation between the APOE4 gene and poor outcomes after ischemic stroke.

An allele with a long and sordid history

The Relationship Between ApoE and Alzheimer's

Alzheimer's disease is the most typical form of dementia. It is a progressive disease that begins with mild memory loss, leads to profound cognitive deficits, and ends with death. 10% to 14% of adults over 65 have some form of Alzheimer's. There is no known cure. Carriers of the APOE4 gene have a significantly greater likelihood of developing Alzheimer's disease.
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Other than its well-known association with Alzheimer’s disease, the APOE4 allele, which codes for the ApoE4 apolipoprotein variant, is associated with unfavorable outcomes in other neurological problems as well, including Parkinson’s disease [1] and amyotrophic lateral sclerosis (ALS) [2]. It is even associated with worse outcomes after acute injuries, such as brain bleeds [3].

However, the relevant data on stroke is muddled and contradictory. These researchers hold that some previous studies on the subject had small sample sizes and confounding factors that impaired the results. These researchers, therefore, sought to take another look at the subject, focusing on outcomes three months after acute ischemic stroke.

A four-figure dataset

Between January 2017 and March 2020, 2,295 people were screened for APOE genotype. 2,001 of them received 3-month follow-ups. 72 people with thrombosis-related issues were excluded. Of the remaining 1,929 people, almost two-thirds had two copies of APOE3, with most of the others having at least one copy of APOE3. Dual carriers of APOE4 and APOE2, along with APOE4/APOE2 carriers, made up less than 4% of the total sample.

People with at least one copy of APOE4 were significantly more likely to have biomarkers of inflammation along with increased LDL cholesterol and triglycerides. Other biomarkers were not found to be statistically significant.

Using the modified Rankin scale to assess disability and death, the researchers found that more than two-fifths of APOE4 carriers were at least slightly disabled, compared to less than one-sixth of noncarriers. Nearly a third of carriers were at least moderately disabled, but only a tenth of noncarriers were. A tenth of carriers had died within the three months, compared to less than 2% of noncarriers.

Interestingly, inflammation was found to be a significant contributing factor only among APOE4 carriers. APOE4 carriers in the highest quartile of the inflammatory biomarker NLR were found to be almost twice as likely to have poor outcomes.

Conclusion

While APOE2 was not differentiated from APOE3, this research seems fairly conclusive in its findings, showing that an allele known for poor outcomes in other areas is connected to poor outcomes in acute ischemic stroke. The logical question is whether or not anything can be done about it. If APOE4 can be properly classfied as a genetic disease, gene therapy or mRNA-based therapies may be worth the effort in minimizing human suffering and maximizing healthy lifespan.

Yes I will donate❤️

Literature

[1] Kim, R., Shin, J. H., Park, S., Kim, H. J., & Jeon, B. (2020). Apolipoprotein E ε4 genotype and risk of freezing of gait in Parkinson’s disease. Parkinsonism & Related Disorders, 81, 173-178.

[2] Chio, A., Brunetti, M., Barberis, M., Iazzolino, B., Montuschi, A., Ilardi, A., … & Calvo, A. (2016). The role of APOE in the occurrence of frontotemporal dementia in amyotrophic lateral sclerosis. JAMA neurology, 73(4), 425-430.

[3] Biffi, A., Murphy, M. P., Kubiszewski, P., Kourkoulis, C., Schwab, K., Gurol, M. E., … & Rosand, J. (2019). APOE genotype, hypertension severity and outcomes after intracerebral haemorrhage. Brain communications, 1(1), fcz018.

Date Posted: January 19, 2023

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Selfish, Reckless, Satanic: Life Extension in Movies

In the much-awaited sequel to the movie Avatar, there is a passing, peculiar mention of life extension. This mention, as can be expected, is negative. In the movie, the greedy, nature-destroying humans hunt a local whale-like species for several ounces of precious liquid secreted by the animals’ brains.

Why? Because this liquid stops aging, which makes it “the most valuable substance in the universe”. So valuable, in fact, that the hunters do not hesitate to kill the “whales” who possess humanlike levels of intelligence and never fight back because in their culture, killing is a taboo. You can start crying now.

The motif of life extension and immortality is probably as ancient as art itself. In the oldest known epos, Gilgamesh, the protagonist, pursues but cannot achieve immortality. Since then, art has been fascinated with life extension, mostly not in a good way.

In the movie Three Thousand Years of Longing, the main character says after being offered three wishes by a jinni: “There’s no story about wishing that is not a cautionary tale”. The same is true for every tale about life extension and immortality. Is it surprising, then, that even today, people harbor deep suspicions and stunningly inaccurate perceptions about geroscience?

Just how bad is it?

A few years ago, Mair Underwood, a sociologist at the University of Queensland in Australia, published a paper that sums up the movie industry’s attitudes toward life extension. To do so, she analyzed 19 movies that deal with life extension, shot between 1973 and 2011.

Underwood found that pursuing life extension was almost universally portrayed as unnatural, arrogant, secretive, selfish, reckless, godless, heretical, and, in one instance, satanic. Even when the scientists in such movies are driven by the purest intentions, the pursuit of longevity does not end well.

According to the paper, “the audience is actively discouraged from sharing enthusiasm for life extension… and from identifying with life extension scientists and those who choose life extension”. Extended life is presented as void of value and meaning, a “nightmare”, a “curse”, and “not really living”.

A prominent theme was that life extension would exacerbate social divides and that access to it would be unfairly distributed. “With death presented as a necessary part of life that adds value”, the paper notes, “and the acceptance of death presented as bringing true joy, it is hardly surprising that mortality is depicted as more valuable than immortality”.

While science fiction is not expected to lean towards the “science” part, it is worth noting that the portrayal of the scientific aspect of life extension in Avatar: The Way of Water and in most other movies is highly unrealistic. We know now that there exists no magic pill or substance that can singlehandedly stop or reverse aging.

Aging is a complex phenomenon that requires combination approaches, the first generation of which are being developed right now. Even if we were to find an animal-sourced anti-aging substance, we would be able to synthesize its active ingredients. No killing of intelligent whales would ever be required.

The wider context

Interestingly, like the Russian doll (the real doll, not the eponymous Netflix series), the small anti-longevity motif in Avatar: The Way of Water is nestled inside a wider anti-progress narrative.

Humanity has a horrible history of destructive practices in colonization, but at least its worst forms are behind us now. Why would future humans, after mastering interstellar flight, bring back old colonial horrors, complete with merciless subjugation of “lesser” conscious beings, rampant exploitation of natural resources, and whaling – something that was banned in the late 20th century? Why would our moral principles deteriorate rather than improve with time, in defiance of humankind’s whole history? Theoretically, that’s possible, but Avatar: The Way of Water provides no explanation for that; it is just assumed.

Juxtaposed with that is the ethos of a beautiful primeval culture living in perfect harmony with nature without ever exhausting its resources. Historical reality, however, is quite different. Early humans wreaked havoc on ecosystems wherever they went, driving multiple species into extinction, especially large ones. Megafauna of islands such as Tasmania and probably Australia suffered the most from hunting and burning of forests. Early humans multiplied and did everything they could to survive without caring too much about the environment.

Our ancestors were also largely helpless against diseases, which led to short lifespans and lots of suffering. Their religious and cultural practices often included intergroup and intragroup violence, and their knowledge of the world was rudimentary at best. We might have something to learn about sustainability from some hunter-gatherer practices, but romanticizing early humans, while simultaneously painting technological and scientific progress in grim colors, does humanity a great disservice.

Real-world consequences

In 2013, an expansive poll by Pew Research Center asked Americans whether they would want to take a pill that would extend their life by decades. This is good wording, since it implies neither immortality nor insignificantly small life extension. Still, most respondents answered “no”. A majority also thought that life extension of this kind was bad for society.

This is baffling. During the last century, average life expectancy grew by several decades – and no one seemed to protest. Why would people think that repeating this feat is a bad idea both for society and for them personally?

On one hand, people as individuals and humanity as a whole consider death a tragedy and try to avoid it. Innumerable resources are spent on keeping people alive for as long as possible, be it via seatbelts or cancer therapies. However, the same idea framed as “life extension” is seen as dubious, calamitous, and even nefarious. It is likely that the way life extension is portrayed in mass culture has something to do with this. Way too often, Hollywood chooses to scare rather than to inspire, because fear and simplistic tropes sell well.

However, this misrepresentation has real-life consequences. Moviegoers are also voters. Stem cell research was stifled in the US for years for political reasons, and while some concerns about genetically modified organisms might be justified, it is becoming increasingly clear that impeding research into genetically modified organisms does more harm than good. Both of those scientific fields can save millions of people from death and suffering, but their potential pales in comparison with that of geroscience.

For millennia, humanity could not even come close to conquering age-related diseases, so life extension remained the stuff of myths and legends. Another piece of ancient writing comes to mind: Aesop’s fable of the fox and the grapes, where the fox, being unable to reach the high-hanging grapes despite much trying, walks away declaring that he wasn’t into those sour grapes anyway.

In the same way, fear of death probably pushes people into embracing it and distancing themselves from those who attempt to rebel against “the ways of God and nature”. Art has always been happy to pluck those strings.

We are not the villains

Today, however, when scientists are finally on the cusp of actually slowing, if not defeating, aging, such attitudes seem outdated, unwarranted, and outright harmful. Thankfully, the tide is turning, and Avatar: The Way of Water might be one of the last movies to use life extension as a scarecrow. Some others, including other Disney content such as Thor and the Eternals, already abandon this trope in favor of a more positive vision of life extension.

We have arrived at a point where geroscience is ready to spread its wings, but it needs society to stand behind it. Significant lifespan extension raises serious questions, and it’s possible to have books and movies that thoughtfully discuss the relevant challenges while remaining scientifically sound. There is much to say about how life extension would affect the fabric of our society and how to ensure equal distribution of future life-extending therapies, which are certainly going to be addressed similarly to, and have the same challenges as, other medical interventions.

However, mad scientists, malicious billionaires, and greedy whalers squeezing magical anti-aging liquid from a giant alien’s brain? Give me a break. Yes, moviemakers need villains, but they should choose their villains more carefully. The arts have a long history of reinforcing harmful stereotypes about sex, race, and culture. Let’s not do that to people working towards healthier, longer lives.

Yes I will donate❤️

Date Posted: January 18, 2023

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Questioning the Usefulness of Model Organisms

In a new review paper published in GeroScience, the researchers explored the translatability of anti-aging interventions across species and received somewhat alarming results [1].

Necessary, but not the best

Model organisms have been widely and successfully used to understand the molecular processes driving disease pathologies, identify drug candidates, and test therapeutic interventions.

Modern drug development is composed of several stages, including preclinical studies in which drug candidates are tested in animals for their safety and efficacy and the right dosage and administration route are determined.

Unfortunately, the vast majority of drug candidates fail for various reasons. The incomplete translatability of results obtained from preclinical species to humans is one of them. After all, 30-40% of drug candidates fail at Phase 1 [2,3]. Likewise, potentially effective therapeutics might never even enter clinical trials due to their failure at the preclinical stage.

Much effort is being made to substitute or augment drug testing in animals with such approaches as 2D and 3D in vitro models, organoids, and in silico methods. Nonetheless, the complexity of human physiology means that it is often necessary to use similarly complex models: other living organisms.

Given that aging is an even more difficult problem than any disease, it is of paramount importance to determine how representative animal studies are of what is going on in an aging human body.

To address this issue, the authors of this review assessed if lifespan-extending compounds identified in invertebrate models, such as Caenorhabditis elegans worms and Drosophila melanogaster flies, are also effective in mice. This analysis gives a hint to the translatability of successful anti-aging lab animal interventions to humans.

Three lab musketeers

The researchers first used the DrugAge database, which contains information about compounds that extend the lifespan of all three model organisms: mice, flies, and worms.

They identified 37 compounds that extend lifespan in mice and either flies or worms. Their analysis shows that predicting the beneficial effect of interventions in mice based on data from flies and worms is not significantly more useful than just picking the compounds randomly from the list. The predictive power for Drosophila was higher than for Caenorhabditis.

Although the sensitivity of prediction was relatively high, i.e. 94% and 86% of compounds that extend lifespan in mice also do so in flies and worms, respectively, the specificity was extremely low. This means that it is impossible to know what doesn’t work as a life-extending intervention in mice based on the data from flies and worms.

More data, similar results

The researchers then complemented this analysis with a separate approach in which they took the results from the Interventions Testing Program (ITP) in mice, Caenorhabditis Interventions Testing Program (CITP), and Drosophila studies.

Using these datasets, they identified 20 compounds that extend lifespan in mice and either flies or worms. Similarly to their first analysis, they show that selecting anti-aging interventions for mice based on data from invertebrates is not significantly better than selecting the compounds at random.

It is conceivable that the drivers of aging are different between invertebrates and mammals. The translatability from mice to humans might be better simply because the same organs and morbidity-driving pathologies are present in both.

On the other hand, unlike mice, humans are a long-lived species, and it is unclear how much we can safely infer about the effectiveness of human anti-aging interventions based on mouse data.

Abstract

A growing number of pharmaceutical and small molecule interventions are reported to extend the lifespan of laboratory animals including Caenorhabditis, Drosophila, and mouse. However, the degree to which these pro-longevity interventions are conserved across species is unclear. Here, we took two approaches to ask the question: to what extent do longevity intervention studies in Caenorhabditis and Drosophila recapitulate effects on mouse lifespan? The first approach analyzes all published reports on longevity in the literature collated by the DrugAge database, and the second approach focused on results designed for reproducibility as reported from the NIA-supported Interventions Testing Program (ITP) and the Caenorhabditis Interventions Testing Program (CITP). Using published data sources, we identify only modest sensitivity and specificity of Drosophila interventional studies for identifying pro-longevity compounds in mouse lifespan studies. Surprisingly, reported studies in C. elegans show little predictive value for identifying drugs that extend lifespan in mice. The results therefore suggest caution should be used when making assumptions about the translatability of lifespan-extending compounds across species, including human intervention.

Conclusion

This review paper highlights the importance of studying age-related phenomena in the organisms that researchers intend to manipulate them in. The translatability of results from one species to another, especially for distantly related animals, is clearly limited for lifespan-extending interventions.

Model organisms are still invaluable tools to discover basic molecular processes and screen for potential anti-aging therapeutics. Nevertheless, new approaches to studying aging and developing ways to interfere with it directly in humans could be the innovations that the field desperately needs.

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Literature

[1] Bene, M. & Salmon, A. B. Testing the evidence that lifespan-extending compound interventions are conserved across laboratory animal model species. Geroscience (2023) doi:10.1007/s11357-022-00722-0

[2] Takebe, T., Imai, R. & Ono, S. The Current Status of Drug Discovery and Development as Originated in United States Academia: The Influence of Industrial and Academic Collaboration on Drug Discovery and Development. Clin. Transl. Sci. 11, 597–606 (2018)

[3] Mullard, A. Parsing clinical success rates. Nat. Rev. Drug Discov. 15, 447 (2016)

Date Posted: January 17, 2023

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The Microbiome Might Affect Motivation for Exercise

Scientists publishing in Nature have found that compounds produced by some types of gut bacteria can influence dopamine levels in the brain and, as a result, might influence motivation to go on a morning run [1].

We’ve got company

We tend to think of ourselves as single organisms, but every human body serves as a home to trillions of other living things: bacteria of various species. Until recently, those microscopic squatters were not getting the attention they deserved. During recent years, there has been a boom in microbiome studies, linking the inhabitants of our guts to neurodegenerative [2] and cardiovascular diseases [3], cancer [4], and inflammaging [5]. We now know that microbiome composition differs significantly among individuals, contributing to the variability in health risks and fitness [6].

Exercise is one of the most potent anti-aging interventions known to humans. Most people know they should exercise, and many do, but motivation remains a serious issue. What’s easy for some is daunting for others. The reasons for this variability in motivation are poorly understood and usually catalogued under the vague label of “personality traits”. However, this study suggests that those differences might have a lot to do with the microbiome.

Do you have the guts to go on?

The researchers started with genetically diverse mice and meticulously phenotyped them, accumulating thousands of data points per animal. They learned that genetic differences played only a minor role in the variability in both voluntary and forced exercise capacity. They then used machine learning to identify variables that were strongly predictive of this capacity. Interestingly, the results of 16s rDNA analysis, which is commonly used to identify bacterial strains in the microbiome, were among the most well-correlated with endurance.

The researchers then performed a series of microbiome depletion and transplantation experiments. Sweeping microbiotal ablation with broad-spectrum antibiotics led to a decrease in exercise capacity. When microbiota was transplanted from donor mice to germ-free mice, the performance levels were highly correlated between the donor and the recipient.

The scientists then continued to experiment on genetically identical B6 mice to exclude factors other than microbiome composition. They tried various narrowly acting antibiotics and found that only neomycin had not impaired physical performance. The researchers again turned to 16s rDNA sequencing and identified several members of the Erysipelotrichaceae and Lachnospiraceae families as possible drivers of exercise performance.

Gut-brain dopamine signaling

However, muscle function and oxygen consumption turned out to be largely similar in microbiome-depleted mice and in controls, so the researchers decided to investigate the motivational pathway.

They found that in striatal neurons (the striatum is a part of the brain central to movement control), levels of dopamine, a major regulator of the drive for physical activity, were elevated by exercise in mice with intact microbiota, but not in antibiotic-treated mice – except those treated with neomycin. Those post-exercise spikes in striatal dopamine levels were restored by the same microbiotal transplants that had improved exercise performance, but not by other types of bacteria. Inhibition of dopamine by other means recapitulated the effects of microbiome depletion.

How exactly did the gut communicate with the brain? Experiments ruled out the possibility that this communication was carried out by metabolites in blood, so the researchers turned their attention to nerves. Their results suggest that fatty acid amides (FAAs) produced by some types of bacteria trigger neuronal signaling that ultimately results in increased dopamine levels in the striatum. FAA-fed mice with depleted microbiomes showed improved exercise ability.

Moreover, the researchers were able to engineer an FAA-producing string of E. coli. Mono-colonizing mice’s guts with this strain (but not with regular E. coli) rescued their exercise performance. The bottom line is that when there are few FAA-producing bacteria in the gut, this seems to blunt the exercise-associated dopamine surge, leading to diminished motivation to exercise.

Conclusion

This study increases our understanding of the diversity of microbiota and their importance for human health and fitness. If the researchers are correct and if these results translate to human beings, people might soon be able to increase their motivation to exercise by consuming specific strains of bacteria or FAAs directly.

Yes I will donate❤️

Literature

[1] Dohnalová, L., Lundgren, P., Carty, J. R., Goldstein, N., Wenski, S. L., Nanudorn, P., … & Thaiss, C. A. (2022). A microbiome-dependent gut–brain pathway regulates motivation for exercise. Nature, 612(7941), 739-747.

[2] Chen, C., Liao, J., Xia, Y., Liu, X., Jones, R., Haran, J., … & Ye, K. (2022). Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation. Gut.

[3] Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020). Gut microbiota and cardiovascular disease. Circulation research, 127(4), 553-570.Chicago

[4] Helmink, B. A., Khan, M. A., Hermann, A., Gopalakrishnan, V., & Wargo, J. A. (2019). The microbiome, cancer, and cancer therapy. Nature medicine, 25(3), 377-388.

[5] Fransen, F., Van Beek, A. A., Borghuis, T., Aidy, S. E., Hugenholtz, F., van der Gaast–de Jongh, C., … & De Vos, P. (2017). Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Frontiers in immunology, 8, 1385.

[6] Clauss, M., Gérard, P., Mosca, A., & Leclerc, M. (2021). Interplay between exercise and gut microbiome in the context of human health and performance. Frontiers in Nutrition, 305.

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