Treating Aging as a Disease

Date Posted: February 6, 2018

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Aging and cancer are closely linked, with the latter being, more often than not, a consequence of the former. Cancer is caused by the aging hallmark of genomic instability, and the two are intertwined. While it is true that young people can get cancer, it is a disease that generally affects older people; indeed, beyond 60, the risk of cancer rises greatly.

Society often talks about the search for a cure for cancer but rarely considers the root of that disease: the genomic damage that gives rise to uncontrollable cell division and the immortalization of mutant cells. It is therefore quite irrational that some people consider cancer to be a disease but rarely accept that the aging processes behind it are also pathological and could potentially be directly treated to prevent cancer in the first place. These processes are not given disease names, but they drive pathology and the appearance of disease. We explore this topic in more detail here.

Ten years ago, the idea that aging might be treated just the same way as a disease was often the subject of ridicule and mockery; however, things have definitely changed since then. More recently, journalists have taken the topic more seriously, there are more articles exploring the subject, and, on the whole, the level of mockery has fallen. This is likely no surprise to those of you who have been following the field for more than a few years, given its increases in funding, investment, and scientific publications.

“If you can control both the environment and the genetics, you can get people that live youthful healthy lives for exceptionally much longer than others. In industrialised nations, most of the diseases are due to age-related diseases and I think those too can be handled.” – Professor George Church

A great example of this change is the number of popular-media articles that have appeared in the last year or two about clearing senescent cells using senolytics. This is excellent news because senolytics are a true repair-based approach to aging and are now being developed by several companies with serious investment behind them.

“We want to fix the things we don’t like about the changes that happen between the age of 30 and the age of 70” - Aubrey De Grey

The ambitious quest to cure aging like a disease

Today, I would like to draw your attention to an article in the BBC, which, in all fairness, is pretty comprehensive in its discussion of the field. It is also nice to note that, in general, this article is also positive about the prospect of doing something about aging.

Of course, no discussion about the potential of a future free from age-related diseases would be complete with the other side of the coin. More often than not, journalists feel almost compelled to include a counterpoint to people advocating for healthier and longer lives through science and technology. The tired old arguments are frequently included for the sake of balance, including the idea that we should just accept aging and suffering as natural and not try to do something about it.

Extending human lifespans by decades or even hundreds of years will present us with some difficult social realities. As BBC Future has explored before, there could be major societal impacts if we all start living longer. There are some that fear greater longevity could lead to swelling populations and raise doubts that our planet could support such numbers.

I am happy to see that such concerns do not dominate this article and that the actual science, progress, and figures working in the field are given more of the spotlight. There is almost no doubt that these disruptive technologies will create challenges for society, but, by the same token, I am confident that, as a society, we will adapt to them and create a better world as a result. Of course, experiencing challenges and finding solutions to them is what mankind has been doing since we first formed societies, and the arrival of rejuvenation biotechnology will be no exception to this rule.

Conclusion

It is refreshing to see a more positive portrayal of the field, especially in such high-profile media as the BBC. More of these kinds of articles are sure to follow as we draw ever closer to the arrival of the technology that could potentially end age-related diseases. A healthy, long life, free from the diseases of old age, is the kind of future that people working in this field want, and hopefully, the greater portion of society will soon agree with us.

Date Posted: February 5, 2018

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A Potential Blood Test for Alzheimer’s Disease

A simple technique to measure the amount of amyloid beta in the brain could improve diagnosis and drug trials for Alzheimer’s disease, according to the results of new research.

A simple blood test

Japanese researchers led by Dr. Katsuhiko Yanagisawa have published a new study suggesting that a screening test could help to boost the success rate of Alzheimer’s drug research. The research team has shown that a simple blood test can accurately measure the amount of amyloid beta, a protein that appears in the early stages of Alzheimer’s disease.

Amyloid is a typical pathological feature of Alzheimer’s disease, so being able to discern how much amyloid is present is key when designing optimal clinical trials. Currently, the only way to measure amyloid accumulation in a living person is either via an expensive positron emission tomography imaging (PET scan) or by taking a sample of cerebrospinal fluid (CSF) via a lumbar puncture, or spinal tap. A blood test would be a far less invasive and costly procedure to help determine how much amyloid is present in a patient.

The researchers believe that suficient amounts of amyloid beta penetrate the blood-brain barrier and enter the bloodstream to be a reliable measure of cognitive function. The hope is to replace the current, costly analysis methods with a simple, cost-effective way to detect preclinical Alzheimer’s and disease progression while improving clinical trials.

In order to measure the amyloid present in the bloodstream, the research team used a technique known as immunoprecipitation with mass spectrometry, which uses antibodies to bind to target proteins. The study included 121 people from Japan and 252 from Australia; of this group, there were people with normal brain function, mild cognitive impairment and Alzheimer’s disease.

The researchers noted that the amount of amyloid present in the bloodstream correlated directly with the level of cognitive impairment. The level of blood amyloid also correlated with results from PET scans and spinal fluid samples from the same patients; this confirms that the blood test is effective.

The researchers are now continuing their study and expanding it in the hopes that they can bring an amyloid blood test closer to standard clinical use.

Conclusion

Having a reliable, non-invasive, and cost-effective biomarker for Alzheimer’s disease is a great result for clinical trials and drug development and may even find utility with home users who wish to monitor their health. We wish the researchers the best of luck and hope that soon, this test will be accepted as standard medical practice.

Literature

[1] Akinori Nakamura, Naoki Kaneko, Victor L. Villemagne, Takashi Kato, James Doecke, Vincent Doré, Chris Fowler, Qiao-Xin Li, Ralph Martins, Christopher Rowe, Taisuke Tomita, Katsumi Matsuzaki, Kenji Ishii, Kazunari Ishii, Yutaka Arahata, Shinichi Iwamoto, Kengo Ito, Koichi Tanaka, Colin L. Masters & Katsuhiko Yanagisawa (2018). High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature doi:10.1038/nature25456

Date Posted: February 5, 2018

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The Misconception of the Two Deaths

When we talk about life extension, we mean people living much longer than they do now, and, more importantly, people who are healthier for longer. For example, we mean being 120 with the health of a 30-year-old. Hang on, though—hasn’t a person who is 120 years old already more than lived their life? Hasn’t that person’s time more than come?

News flash: you haven’t lived your life until you’re dead, and even then, you might not necessarily have crossed off all the items on your list. So, no, there is no such thing as an age when you have, by definition, “already lived your life”—not 80, 90, 100, nor any other. What people actually mean when they say that someone has “already lived their life” is that, in their opinion, that person has lived long enough, and thus he or she might as well, and perhaps even should, die.

People who, for one reason or another, fear a world without aging tend to say things like that. Personally, I am much more afraid of a world where other people get to tell you when your life has been long enough, and, consequently, I tend to say that the only one who should have the right to decide when you’ve lived long enough, if ever, is you—not other people, not nature, not an imaginary greater good. You.

However, I don’t think that these people just like telling others how long they should live; rather, it is my opinion that they fall prey to a common misconception, which I like to call the misconception of the two deaths.

How many kinds of death are there? Well, as a first approximation, you might be tempted to answer “two”; there is death by old age, and then there are other causes. (In case you’re wondering, these are exactly the two deaths that give the misconception its name, so, as you might guess, this answer is wrong.) Then, if one wants to be pedantic, one could start listing examples of the other causes, and thus the answer might easily become “many”. This is wrong too, by the way.

The correct answer is one. There is only one kind of death, namely death by “something essential in your body stopped working.” Then, of course, we can go into details, such as what specifically stopped working and why, but they’re indeed just details, useful mainly to any doctors who were trying to prevent your death or to the coroner to write on your death certificate.

Let me give you an example. Suppose I got shot in the heart. (Hopefully that won’t happen.) What killed me would be the fact my heart stopped; in turn, what caused my heart to stop was the bleeding hole that the gunshot punched into it. Similarly, if I died of a heart attack, the cause of death would still be that my heart stopped, but what caused it to stop would be something else—probably, I read a pro-aging article or something like that.

So, when people say that someone has died of old age, they’re just using shorthand to say that something essential in that person’s body stopped working, and the cause of that failure was something that has a higher likelihood to happen to you past age 70 or so.

What does this have to do with the whole issue of whether somebody has already lived their life or not? In my opinion—and, mind you, it’s just my opinion that we’re talking about—it has everything to do with it. I think that many people assume that all the deaths in the “other causes” category are not okay in the sense that, when you die of one of those, you have not yet lived your life; conversely, when you die of old age, they think you have. Probably, it’s because they think that the so-called death by old age:

happens of its own accord, without external intervention;
lets you live for as long as “naturally” possible;
generally allows sufficient time for you to do all that is considered standard for human life (study, work, have a family, etc.);
occurs at a point when you’re generally not healthy enough to do much else;
is inevitable, which adds to the feeling that this is how it ought to be.

Point number one is only partially true. Sure enough, even with the healthiest of lifestyles, human genetics is such that you can’t really hope to live much more than 120 years (without more radical interventions, such as rejuvenation biotech). However, sufficiently unhealthy lifestyles can make the very same diseases of old age happen sooner. This means that the way you live your life affects how long your life will be; therefore, it’s not true that death by old age only happens of its own accord. Your external interventions, even something as relatively trivial as what you eat, can and do make a difference.

Consequently, point number two is not true. Even without opening the worm can of the meaning of “natural”, since the age at which the diseases of aging strike (and thus kill) you is influenced by your actions, it is by no means guaranteed that you couldn’t have lived longer than you did if only you had made different lifestyle choices, even something as simple as eating in a more healthy way.

Points three and four are the truly interesting ones here. Currently, the life of an average human entails a number of standard milestones whose achievement pretty much defines how much of a successful, or at least “normal”, life one has lived. We’re talking mainly about studying, having a career, starting a family, perhaps becoming good at any hobbies you might have, having grandkids, and then “enjoying” your “golden years”.

These milestones dictate the rhythm of our lives to such an extent that not only do people cast suspicious glances at you when you fail to deliver on schedule (“You’re thirty already; when are you going to have kids?”, “Isn’t it about time you settled down and had a career?”, etc); but also, most people think that, once these goals are accomplished, there wouldn’t be much else to look forward to even if you were healthy enough to accomplish more, and as per point four, you’re not anyway.

These two points are pretty much the very essence of this whole “having already lived one’s life” thing; past the standard milestones, there isn’t anything else worth doing, and even if there was, you’re in no condition to do it. Hence, you’ve pretty much already lived your life. One might even think that human lifespan is just long enough to let us do precisely all we want or need to do.

This is completely backwards, of course. Human lifespan didn’t stretch and shrink just enough to perfectly accommodate our favourite milestones. Rather, we adapted to our lifespan, planning and scheduling our lives, our societies, and our policies around our biological limitations. Our standard milestones and their chronological progression are a consequence of our average healthspan and lifespan, not vice versa. The “normal” course of life outlined above is by no means the right one, better than others, or what ought to be. It’s just all we could afford under the circumstances. For some people, it might be enough; for others, it might be terribly insufficient. However, I do think that, given the option, many people who profess their satisfaction with the current state of affairs might seriously reconsider.

This brings us to point five, which, up until this moment in history, has made the whole discussion moot; whether it occurs sooner or later, death by old age is inevitable. So, not only is there little point discussing ifs and buts, but maybe, if things stand the way they do, there’s a good reason. Isn’t it comforting to think that, if we’re all doomed to die, there’s a good reason why this is so? Pretty much the way that a fervent believer may not understand why God let so many innocents die in a terrorist attack, or a war, or a catastrophe, but is relieved to think He must have had a good reason to do so, many people think old age comes to take us away for some higher purpose—preventing overpopulation, boredom, or whatever.

With the advent of pioneering rejuvenation biotechnology, the inevitability paradigm of point five is starting to crack, and as it will become clearer and clearer that defeating aging is possible, I argue that many people will do away with the idea that if aging exists, then it ought to, without even bothering going through the (obvious) reasons why this idea is fallacious. The previous four points, as we’ve seen, rest on seriously shaky grounds, and taken all together, these points don’t make death by old age any more acceptable than any other kind of death, and don’t mean in any way that when you die of aging, you had already lived your life and couldn’t—or shouldn’t—ask for more.

Who knows; maybe, there will come a point when you’ve already lived your life. However, when that point is, and whether and how your life should end, I think should be only in your hands.

Date Posted: February 2, 2018

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Could Klotho Treat Dementia by Targeting Aging Itself?

Researcher Dr. Dena Dubal, from the University of California San Francisco, is considering a new approach to combat neurodegenerative diseases, such as Alzheimer’s disease and dementia, using a protein known as klotho.

Aging is the foundation of age-related diseases

Instead of trying to understand each of these diseases and the complex mechanisms unique to both, she considered what all these conditions have in common; the answer, of course, is aging.

Like all age-related diseases, these conditions develop because of the aging processes that damage us and prevent our bodies from repairing themselves effectively. These processes have been defined clearly in the Hallmarks of Aging, which divides aging into a series of processes and offers potential solutions to each[1].

Aging is the greatest risk factor for neurodegenerative diseases and one of the greatest challenges that the biomedical field faces. Dr. Dubal believes that our current understanding of aging could help us to combat neurodegenerative diseases. She asks, “Why don’t we just block aging?” In other words, she suggests targeting the aging processes to potentially halt multiple age-related diseases.

From Greek myth to modern science

With this in mind, she got interested in a protein called klotho, which is named after the Greek legend of Clotho, a mythological figure who created the thread of life and had control over when gods and mortals would die.

The klotho protein was originally documented in 1997 by researchers in Japan[2]. During this study, they also discovered the suppressive role that klotho has against some aspects of the aging process. They also learned that defective klotho gene expression in mice results in a syndrome similar to human aging, including a shorter lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema.

It was later discovered that transgenic mice that produce more klotho live longer [3-4]. This was also confirmed in humans, as people who produce more klotho tend to live longer than people who produce less.

The klotho protein functions as a circulating hormone that binds to a cell-surface receptor and suppresses the intracellular signals of insulin and insulin-like growth factor 1 (IGF1); it is an evolutionarily conserved mechanism for extending lifespan. Klotho influences part of the aging hallmark known as deregulated nutrient sensing, one of the reasons we age.

Klotho is neuroprotective

Back in 2014, Dr. Dubal wanted to find out if klotho levels help our brains remain healthier as we age and reduce the impact of cognitive decline. She and her research team discovered that in both mice and humans, more klotho means better cognition, meaning that it is neuroprotective[5].

In humans, only around 20 percent of people have high levels of klotho, but Dr. Dubal wants everyone to benefit from its neuroprotective effect. Her research team wants to test the potential of klotho as a neuroprotective therapy.

The klotho protein exists in two distinct forms; the first is anchored in the cell membranes of the organs, mostly in the brain and kidneys, and the second form is seen when the protein becomes detached from its anchor and then floats around the bloodstream.

Dr. Dubal’s team discovered that they could simply inject this second form of the protein directly into mice and receive the same effect that genetically high klotho levels have.

Perhaps even more impressive was that the mice treated showed improved brain function within just four hours, and this treatment worked in young mice, old mice and an Alzheimer’s mouse model.

The next step for Dr. Dubal and her team will be to work out how klotho interacts with the brain without it crossing the blood-brain barrier. Once this information is discovered, it could then lead to a klotho therapy for humans to improve cognitive function and protect the brain from age-related diseases.

In a University of California San Francisco article, Dr. Dubal said, “For humans, the end game really is: how can we increase our ‘healthspan?’” She continues, “And that may go hand in hand with an increase in lifespan, because the things that help us to live longer are also the things that help us to live better.”

Conclusion

Once again, it is good to see respected researchers talking about combating age-related diseases by targeting the aging processes themselves. This approach has the potential for treating or preventing multiple diseases at once, and it is a shift in thinking that the medical industry is starting to accept. The sooner the majority of researchers take this approach, the sooner we can start to really do something about age-related diseases.

A therapy that influences deregulated nutrient sensing is an interesting prospect and may lead to a viable neuroprotective therapy if a simple injection works on humans the way it does on mice.

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] Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., … & Iwasaki, H. (1997). Mutation of the mouse klotho gene leads to a syndrome resembling ageing. nature, 390(6655), 45.

[3] Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., … & Shimomura, I. (2005). Suppression of aging in mice by the hormone Klotho. Science, 309(5742), 1829-1833.

[4] Dubal, D. B., Zhu, L., Sanchez, P. E., Worden, K., Broestl, L., Johnson, E., … & Kuro-o, M. (2015). Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. Journal of Neuroscience, 35(6), 2358-2371.

[5] Dubal, D. B., Yokoyama, J. S., Zhu, L., Broestl, L., Worden, K., Wang, D., … & Ho, K. (2014). Life extension factor klotho enhances cognition. Cell reports, 7(4), 1065-1076.

Date Posted: February 1, 2018

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Rejuvenation Roundup January 2018

The first month of the new year is already behind us, so it is time to sit down and look back at what happened in the rejuvenation world during January; thankfully, there’s plenty of good news to talk about!

Healthy aging is back in WHO’s agenda

You might recall that late last year, LEAF board director Elena Milova wrote about our concerns about WHO’s decision to leave out healthy aging out of its draft programme of work 2019-2023. Luckily, thanks to the efforts of the longevity community, this danger has been averted; as we mentioned in the December 2017 roundup, the vast majority of the feedback that WHO has received through the open consultation on its programme stressed the importance of including aging in the draft. As a result, WHO revised its draft, which now includes several provisions on healthy aging, as discussed here. This is a great achievement of all longevity activists and proves that we can have an influence on public opinion and policymakers. We’d like to thank each and every person who helped us get there!

Record-smashing funds for SENS Research Foundation

You probably recall our excitement last December about the $1 million bitcoin donation made by the anonymous donor running the Pineapple Fund, which pushed SRF’s winter fundraiser well beyond its initial $250,000 goal. You can imagine our (and SRF’s!) amazement when we found out that their digital-currency good fortune didn’t stop there; one more million dollars in bitcoin was donated to SRF by another anonymous donor, and another $2.4 million in Ether were donated by Vitalik Buterin, the cofounder of Ethereum and Bitcoin Magazine. Together with the other winter fundraiser donations, this amounted to a whopping $5,041,134, which makes for a fantastic (late) Christmas present for SRF!

We’re not done congratulating them yet, because SRF was also one of the winning charities of Project4Awesome 2017, as officially announced by John Green in this video. LEAF was not among the winners of this year, but we’re nonetheless extremely happy and excited about the huge increase in popularity of life extension and the large exposure the movement as a whole is gaining!

A digest of articles from FA!

In this article, veteran rejuvenation advocate Reason of the blog Fight Aging! discusses a study suggesting that there comes a point in middle age when exercising cannot reverse the adverse effects of a sedentary life any longer. While exercising yields benefits at any age, and in this sense it’s never too late to get off the couch, some aspects of secondary cardiac aging—that is, consequences of external factors that negatively affect your heart—won’t be undone by exercising when it’s too late. Still, you should always exercise if you can in order to slow down health deterioration.

While most of the damage occurring to our DNA is quickly taken care of by efficient repairing mechanisms, some damage slips through the cracks and manages to accumulate over time. Some of this damage may lead to cancer, but does the rest of the damage matter for aging? Here, FA! points out a paper that puts more weight on the degree to which such damage is replicated, rather than just its occurrence.

LEAF news

In case you haven’t been following the blog too closely lately, here’s a selection of our articles that you may want to go back to have a look at.

Volunteer writer and biomolecular engineer Ariah Mackie discussed deregulated nutrient sensing—one of the hallmarks of aging—in this article. If you want to deepen your understanding of the biology of aging, you should check this one out!

In occasion of his birthday, LEAF President Keith Comito made a present to the life extension community—a video to recap our achievements of the past year and whet our appetite for what’s to come in 2018.

If you’re still among those who are undecided between aging as natural or a condition to be treated, this article by Steve Hill may solve your conundrum, explaining how aging is actually both.

We interviewed Drs. Michael and Irina Conboy on the topic of parabiosis to shed some light on what rejuvenative benefits we can expect from filtering old blood.

The biotech Valley of Death

The folks at Geroscience wrote about something I’ve often noticed myself and surely you have too; all too often, we hear about some new, thrilling biomedical breakthrough only to never hear about it again. This may induce people to remain skeptical about, and at times even show contempt for, research news. (If you’re a Reddit user, you are probably accustomed to cynical comments along the lines of “here’s Reddit’s weekly cure for cancer” on any news on cancer discoveries, for example.) In this video interview, Geroscience’s lead editor Tegan McCaslin and venture capitalist James Peyer discuss what happens when new discoveries reach the “biotech Valley of Death” and the hurdles that make it difficult to leave that dreadful place.

Coming next month

Altered Carbon premiere screening

On February 2, we will host the premiere of the new Netflix series Altered Carbon, showcasing the dark and dangerous world of Takeshi Kovachs, where only the wealthy can re-upload their digitized selves from one clone to another forever. You can have a look at the series’ trailer here.

SENS Research Foundation’s CSO Dr. Aubrey de Grey will be attending the event and hold a Q&A session right before the show. We will also be offering themed drinks and snacks, and there’ll be a chance to mingle with other fans of the series, so don’t miss out! You can find more information and get your tickets here. The event’s revenue will go towards supporting LEAF/Lifespan.io.

AI vs Aging panel

In occasion of the late longevity record holder Mme Jeanne Calment‘s birthday, on February 21, we will host a panel with the MouseAge team on the topic of artificial intelligence in aging research—more details to come. On the same day, due to a suggestion by LEAF volunteer Victor Bjoerk, The Longevity Reporter will host a Facebook event where all participants are invited to show their support for aging research by taking a selfie with Mme Calment’s favourite foods—chocolate and olive oil.

Two Journal Clubs in February

It is our custom to have a Journal Club every month as part of our Lifespan Heroes program, but, unfortunately, January saw us encounter a problem at Cooper Union University, from where the stream is broadcast and presente. This meant that we had to move the scheduled broadcast from January 30th to the 6th of February at 13:00 EST; yes, that’s right, folks, the January Journal Club is in February. On the plus side, it also means there will be two journal clubs in February, as the regular one will also happen on February 27th as normal live on our Facebook page.

Date Posted: January 29, 2018

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The Abolition of Aging – A Book Review

As you might recall, in my review of Ending Aging, I said that the book could have benefited from a more in-depth discussion of the benefits of rejuvenation as well as the concerns and objections often raised against it. Anyone else sharing the same feeling will find what they’re looking for in The Abolition of Aging, by Chair of London Futurists David Wood.

Written in an elegant, clear style, The Abolition of Aging brilliantly accomplishes the difficult task of guiding the reader through all the turns and twists of the topic, explaining in great detail the benefits that would derive from a successful implementation of the “rejuveneering project”—as Wood calls it—presenting all the typical objections and related counterarguments, and—in the words of 3G Doctor Director David Doherty—providing innumerable “stunning references and observations”.

Just like there’s no time to waste if we want to defeat aging in time for currently living people to benefit, Wood wastes no time with lengthy preambles; the very first line of the foreword comes directly to the point, bluntly stating what readers unfamiliar with the topic may find shocking: the possibility of eliminating biological aging is now within striking distance.

Possibly preventing the reader’s reaction, the author immediately gives a preliminary discussion of the traditional responses to his claim: “it’s not possible” and “it’s not desirable”, which Wood ascribes—correctly, in my opinion—in no small part to a great desire to avoid an unpleasant discussion that would force us to reconsider many assumptions on the inevitable finitude of human existence, with which most of us have already made our peace.

To succeed in his task of getting us to snap out of a multi-millenary Stockholm syndrome that pushes humanity to praise the tyranny of old age, Wood resorts to every weapon in his arsenal, making a very convincing case that rejuvenation is very much desirable as well as possible.

Skeptics who assume that the technology necessary to rejuvenate people is centuries away will be surprised to learn about how advanced the field actually is and how much faster it is likely to grow than conventional wisdom would have it. The word of senior scientists who claim that the reversal of aging is nothing but a pipe dream, as Wood warns us, should be taken with a grain of salt: The Abolition of Aging provides plenty of examples of luminaries and eminent experts of the past summarily dismissing scientific theories and technologies that today are well-established and taken for granted by everyone. (Among many such examples, one I really cannot abstain from mentioning is the hilariously wrong 1903 prediction by the New York Times that human flight, if at all possible, would take one to ten million years to come true. Less than 70 years later, not only was human flight commonplace, but human beings had landed on the Moon.)

Nonetheless, Wood’s optimism should not be mistaken for complacency. He makes no mystery that the success of the rejuveneering project is a mere possibility, however likely, and not at all a certainty. Many are the unknowns—scientific, political, societal, financial, and more—that could well thwart our efforts in this direction if we’re not careful. Wood offers advice on how to deal with these issues standing in the way of an aging-free world as well as those that might lurk beyond. After all, the functioning of society as we know it hinges on the existence of aging; our lives, our policies, and our customs are built around it.

Eliminating aging would require a serious rethinking of much of society’s inner workings, and this operation is not free of risks, as Wood rightfully concedes. Great changes for the better often come with potential downsides, but we should not let this deter us; rather, we should appreciate how the fruits to be reaped are well worth the potential risks involved and act now to prevent or mitigate any unwanted consequences. A world without aging would need to be managed in a different way, but that is not a problem.

A particular obstacle on the way to a world without aging is represented by adverse psychology, to which Wood dedicates an entire chapter. Ever since we had the ability to reflect upon ourselves and the human condition, as the author explains, we’ve had to face our own mortality and fear of death. Fear of death is a very useful adaptation to increase the chance that an individual will live long enough to reproduce, but in the case of a highly self-aware species like us, it’s a double-edged sword. Our deep desire to express ourselves, to learn, create, grow, to live, inevitably clashes against the knowledge of our apparently inescapable demise.

If left unresolved, this inner conflict could strike terror so paralyzing that living our lives would be impossible. With no hope of defeating an apparently all-powerful enemy such as death, the young human race had to devise other ways out of this conundrum—psychological expedients to sugar the pill or even make it appear better than the alternative; for some, having children, creating art, changing the world through their work and so on may all offer the comforting thought of their legacy, and thus part of themselves, carrying on at least to some extent; believers have faith that their immortal souls will continue existing even after their bodies will have perished; others assume a world without death would, for one reason or another, be so unbearable that oblivion would be preferable.

These mental devices have existed for so long that they’ve shaped our society and our morals; accepting death has become a sign of wisdom while trying to avoid or delay it when “the right time” has come is seen as a sign of immaturity and selfishness. These views are so entrenched in most people that any attempt to question their validity is likely to trigger aggressive defensive reactions or, sometimes, contempt and ridicule. For these reasons, life extension is not an easy idea to sell. In his detailed discussion, though, Wood provides valuable advice to ease the advocates’ task, listing the dos and don’ts of how to present the subject.

Rejuvenation is not all the book deals with. Wood’s futurist soul fully reveals itself in his vision of the futures of humanity, faith, and death, which are discussed in the chapter “Towards Humanity+” as well as in the possibilities outlined in chapter 12, “Radical alternatives”, such as cryonics, head transplants, and mind uploading. While these ideas are often plagued by abundant hype and unjustified premature enthusiasm, I find that Wood simply presented relevant facts as they are, with an appropriate dose of healthy skepticism where needed but without any undue disbelief. Cryonics in particular, which is usually unjustly regarded as a scam to part rich fools from their money, is presented as a valid backup plan for those who don’t expect to live long enough to see the dawn of rejuvenation; just like cryonics companies themselves, Wood makes no mystery that it is uncertain if bringing back to life cryopreserved patients will ever be possible, despite encouraging successes with transplantation of cryopreserved animal organs. Then again, I would add that if the chances of coming back to life from cryopreservation are uncertain, there’s no chance whatsoever of coming back after being buried or cremated.

Summing up, I believe that The Abolition of Aging is a must-read for experienced advocates and newcomers alike. People who haven’t made up their minds about supporting rejuvenation will be fully equipped to make an informed decision after reading this book, or, at the very least, will be able to research the topic further; advocates will have plenty of references and useful information for their advocacy efforts. Together with Ending Aging, this book answers pretty much all the whats, whens, hows, and whys to the best of our current understanding.

Date Posted: January 29, 2018

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Google’s Calico Announces Discovery Of A “Non-Aging Mammal.”

Completely bald and with wrinkly skin, the naked mole rat is one of the ugliest creatures around but lives an exceptionally long life for a small mammal. It rarely develops the chronic diseases of aging, such as cancer, and lives 10 times longer than regular rats.

The First Non-Aging Mammal

In the first significant announcement from Calico Labs since it was formed in 2013, researchers Rochelle Buffenstein, Megan Smith, and J. Graham Ruby have announced that the naked mole rat is a “non-aging mammal.”

The researchers followed the naked mole rats – housed at the Buck Institute – over a three-decade-long study period. They found that these creatures show hardly any signs of aging, such as problems with their metabolism, heart, or bones. Females do not go through menopause and continue to reproduce into their 30s, which is an amazing feat for an animal that lives at least 30 years of age in captivity. Even the cells in their bodies have a remarkable resistance to oxidative damage caused by free radicals. Small rodents the size of the naked mole rat live for no more than six years.

Senior Principal Investigator Rochelle (Shelley) Buffenstein, Ph.D. spent the early part of her career at the Medical School of the University of Witwatersrand, South Africa, where she studied the naked mole rat for ten years. Principal Investigator J. Graham Ruby, Ph.D. received his doctorate in biology from MIT and performs biometric, biostatistical, bioinformatic, and quantitative genetic analyses of diverse data to decipher the aging process in humans and model organisms. The researchers published their results on Jan 24th in the open access journal eLife[1].

How the Non-aging Mammal Was Discovered

To judge the rate of aging, the Calico team used a mathematical model called the Gompertz-Makeham law of mortality. This statistically validated law states that the risk of death for every mammal increases exponentially with increasing age. The Calico researchers used this model to analyze an existing data set of more than 3000 naked mole rats over a 30-year timespan and found that the small mammals did not conform to the Gompertz-Makeham law. Unlike every other mammal, the mole rats do not face an increased hazard of death with each birthday; as the Calico authors said, “This absence of hazard increase with age, in defiance of Gompertz’s law, uniquely identifies the naked mole-rat as a non-aging mammal.”

Estimated probability of a US person dying at each age (2003.) Credit: Uscitizenjason CC BY SA 3.0

This is astonishing given that all other mammals, including humans, face an increased rate of death with each passing birthday. Consider this hazard chart for US citizens in 2003, in which the mortality rates increase exponentially with age after the age of 30. In contrast, the equivalent chart for the naked mole rat is almost flat.

Caleb E. Finch and Hiram Beltrán-Sánchez, a pair of scientists from the University of Southern California (USC) in Los Angeles, analyzed and commented on the study. Caleb E. Finch, Ph.D. is a molecular biologist in the Leonard Davis School of Gerontology and Dornsife College. Hiram Beltrán-Sánchez is from the Department of Community Health Sciences and the California Center for Population Research.

Commenting on the remarkable results of the study in a companion piece[2], Finch and Beltrán-Sánchez said that the naked mole rat defied the Gompertz-Makeham law, remarking, “their risk of death does not increase as they get older” and “this is unprecedented for mammals.”

Finch and Beltrán-Sánchez said that previous studies of the non-aging mammal suggest that aging creeps in, nevertheless. Naked mole rats can accumulate oxidative damage in their cells and experience muscle wasting. There is also some evidence for small amounts of cancer. But, after reviewing the evidence, the USC authors said, “This would suggest that unlike any other mammal, the naked mole rats have an extremely low rate of aging.”

Finch and Beltrán-Sánchez said that the minimal age-related problems of the mole rat combined with its long lifespan allow it to achieve ‘negligible senescence,’ a phenomenon in which an animal reaches an advanced age without increased mortality or disability.

Other scientists believe that the longevity of naked mole rats is due to the limited oxygen of their subterranean habitat. Because of this environment, their metabolic rates are abnormally slow, and an abundance of repair mechanisms keeps their cells astonishingly youthful.

About Longevityfacts

We have teamed up with our friends at Longevityfacts and will be publishing some of their articles as part of an agreed syndication deal. This article originally appeared here at Longevityfacts.

Literature

[1] J Graham Ruby, Megan Smith, Rochelle Buffenstein, Calico Life Sciences LLC. “Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age.” eLife 2018;7:e31157 DOI: 10.7554/eLife.31157, Jan 24, 2018.

[2] Hiram Beltrán-Sánchez, Caleb Finch. “Life Expectancy: Age is just a number.” eLife 2018;7:e34427 DOI: 10.7554/eLife.34427 Jan 24, 2018.

Date Posted: January 27, 2018

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Taking Care of Your Fibroblasts Might Help You Look Younger

As we age, our bodily functions begin to deteriorate. To some extent, our bodies can cope with these unwelcome changes, but after age 35, some of them become visible. For us living in a world where youth and physical attractiveness are considered an advantage, this gradual loss of young looks can be painful – or maybe even scary, if we don’t know a way to slow down or reverse it.

It is not that physical attractiveness is a value per se for me, but I often hear people say that someone promoting longevity technologies should set a good example; wrinkles, dull skin and hair, and a bloated figure discredit not only the activist but the movement as a whole.

So, I keep an eye on what is going on in the field of aesthetic medicine – especially when it comes close to and crosses with rejuvenation biotechnologies. Last week, I went to one of the flagship research organizations in Moscow – the Human Stem Cells Institute – to interview Dr. Vadim Zorin, the head of the SPRS-therapy project and the developer of a unique approach to skin rejuvenation.

Vadim, thank you very much for finding time to tell our readers about your work. Our community is interested in various approaches to slowing down the aging process. If we recall the Hallmarks of Aging published in 2013, aging of the skin (and other tissues, I suppose), is due to three mechanisms of aging: depletion of the stem cell pool, dysregulation of proteostasis (that is, the cell produces fewer proteins necessary for its normal function, or these proteins are deformed), and cellular aging. Tell us, please, how does SPRS therapy counteract these aging mechanisms?

SPRS-therapy® stands for Service for Personal Regeneration of Skin. It is a combination of personalized medical and diagnostic procedures for skin regeneration when it already carries some signs of aging and other structural changes. SPRS-therapy® is based on the technology of extracting, assessing, cultivating and using autologous (the patient’s own) fibroblasts. We have patented this technology in Russia, the European Union and the United States.

Fibroblasts are the main cellular component of the skin’s connective tissue, maintaining its homeostasis and morphofunctional organization. They perform a number of diverse and complex functions in the skin; they control the composition and structure of the components of the extracellular matrix of the dermis (collagen, elastin, proteoglycans and structural glycoproteins), and their function includes both the production of these substances and their catabolism.

Thus, fibroblasts are a key link in skin biology; they support the homeostasis of the extracellular matrix of the dermis, providing its remodeling and renewal, and they play a significant role in maintaining the physiological state of the other layers of the skin.

As the population of skin fibroblasts ages, the number of cells decreases in the skin of old people. The total number of fibroblasts is reduced by an average of 35%, and their biosynthetic activity decreases. According to G. Fisher et al., 2002, the production of collagen in the skin of old people is, on average, 75% below that of young people. The balance between the processes of synthesis and degradation of the extracellular matrix of the dermis is disturbed. The natural consequence of these processes is a decrease in the thickness and elasticity of the skin and the formation of wrinkles. Hence, the process of skin aging is ultimately caused by a decrease in the fibroblast population and a decrease in their proliferative/synthetic activity, which is naturally manifested by a decrease in the quantitative and qualitative composition of the extracellular matrix of the dermis.

So, the loss of functional fibroblasts seems to be the key enemy of those of us chasing indefinite youth, at least on the outside. How exactly does SPRS-therapy fight against these unwelcome, age-related changes?

The use of cultured autologous dermal fibroblasts (autoDF) allows us to replenish the decreased fibroblast population by introducing specialized, functionally active cells into the skin of the patient.

As early as 1994, American scientists showed that the introduction of autoDF into the skin promotes effective wrinkle correction, and a number of clinical studies have been carried out by both American and Russian scientists to confirm the effectiveness and safety of autoDF in cosmetic medicine.

Building upon this work, we developed our own method to fence, transport, isolate, cultivate, cryopreserve, store and apply autologous fibroblasts for skin rejuvenation. We took it into clinical trials and proved its positive effect. In 2010, the Human Stem Cells Institute (HSCI) in Russia received permission from the Russian Federal Service for Surveillance in the Health Care Sector to use SPRS-therapy to treat age-related and cicatricial changes in the skin. In 2011, the FDA in the United States issued a permit to another company, Fibrocell Science, to use autoDF to correct wrinkles in the area of nasolabial folds (it is called LAVIVTM, or azficel-T).

Through instrumental and morphological studies, we observed an increase in the thickness and elasticity of the skin and a decrease in the number and depth of wrinkles. This indicates that after the transplantation, cultured autoDF cells are fully integrated into the dermis, and their biosynthetic activity persists for at least 12 months. As a result, the microstructure of the dermis is remodeled, increasing its collagen fibers and thus increasing skin hydration, density, and thickness. This particular clinical effect becomes more pronounced throughout the year after the intervention, and it lasts for at least two years. Our results are consistent with the results of research conducted by the American company Fibrocell Science, which also demonstrated a significant decrease in the number of wrinkles and increased skin thickness after the use of autoDF.

Sounds pretty amazing! Of course, someone who is serious about restoring a youthful appearance won’t use just one therapy but rather a combination. This includes plastic surgery and other injection methods, such as the recently popular PRP or fillers. However, your therapy has been clinically tested, so its effect was monitored. What did your patients say, and how many years younger did they look after the course of treatment? How exactly do you measure the results?

It is difficult to say how much younger it is after SPRS-therapy, since such studies have not yet been conducted by anyone, but we can definitively measure changes in the metrics that are “responsible” for the youth and beauty of skin, including its thickness, density and hydration, intensity of pigment spots, and number and depth of wrinkles. Our clinical analysis of the skin’s condition (on a 5-point scale) showed that one month after the injection, 88% of the patients rated the result as “good” and “excellent”, but after 3, 6, 12, and 24 months, it was 100% of patients.

We performed histological studies; simultaneously with the introduction of the autoDF into the skin, we injected our participants in a spot behind the auricle for subsequent biopsies at 1, 3, 6, 12 and 24 months. We conducted morphometric evaluation of the thickness of the dermis and impregnated it with silver nitrate in order to detect newly formed collagen fibers. Our immunohistochemistry studies revealed prolonged biosynthetic activity of transplanted autoDF for at least 12 months, which was expressed in the synthesis of components of the cellular matrix and an increase in the thickness of the dermis by an average of 63% over those 12 months. We also evaluated microcirculation with laser Doppler flowmetry (laser blood flow analyzer), elasticity with cutometry (Cutometer MPA 580, Courage + Khazaka Electronic GmbH), skin texture and wrinkles using the VISIA photometric system (Proctor & Gamble Co), and wrinkle depth by means of optical profilometry (PRIMOS, GFMesstechnik GmbH).

These measurements showed a significant increase in the elasticity and thickness of the skin, a decrease in the intensity of pigment spots, and a decrease in the number and depth of wrinkles.

It is wonderful that we have a way to achieve external rejuvenation. Moreover, this affects not only the condition of the skin but also the common problem of hair loss. As I understand it, this is especially important for men; what is the proportion of the male population among your patients?

About one-third of our patients are men.

Is it possible to restore the pigmentation of hair in people who have already turned gray?

To date, no, it’s not currently possible. This is a very complex process, since physiological graying is associated with the natural aging of other cells, specifically melanocytes, and early graying, as a rule, is due to their death or decreased activity due to hormonal disorders. As a result, the hair is deprived of the pigment, it acquires a porous structure, and the air between the layers gives the affected hair a silvery white hue. We cannot stop the process of graying because melanocytes begin to work even in the prenatal period of human development and gradually regress with age. Every 10 years after the age of 30, their function fades by 10-20% and hair begins to appear with no pigment in the keratin. With the withering away of all the melanocytes supplying melanin to the hair shaft, the hair becomes completely gray.

A more difficult question is whether this approach is applicable to the restoration of other tissues and organs, or does SPRS only allow you to restore the skin? If there are restrictions, then what are they related to?

SPRS-therapy is aimed at restoring only the skin because it is based on the use of skin fibroblasts. However, in the arsenal of our company, there is another authorized technology: SPRG-therapy (patented in Russia in 2010), which is based on the use of fibroblasts of the oral mucosa, which allows the restoration of soft periodontal tissue. So, we can say that this technology can be adapted to some of other cell types, but each new type requires its own set of production processes and, of course, clinical studies.

Last year, our community was enthused by news from the Salk Institute, where due to reprogramming of adult cells with Yamanaka factors, the researchers managed to partially reverse some age-related changes in mice, such as muscular dystrophy or age-related metabolic disorders. What do you think about the combination of SPRS and the short-term application of Yamanaka factors on cell culture? Can the further development of SPRS therapy go in this direction?

Yes, of course, the reprogramming of autologous skin fibroblasts will allow obtaining personalized induced pluripotent cells (iPSCs), which can be considered innovations towards autogenous therapy of a wide range of diseases, and iPSCs are also useful for drug screening. However, it should be noted that, despite the promising therapy options based on autologous iPSCs, this technology is still at an early stage of development. Further research is needed, including a detailed study of the biological and cancer-related safety of these cells, an analysis of their chromosomal stability both in early and late passages, and a complex analysis of their differentiation potential.

At the moment, SPRS therapy is quite expensive; the price for one course of treatment can be more than $5,000. For this anti-aging approach to become available to the masses, the price should be significantly reduced. HSCI has a very positive history with regards to reducing the price of an innovative product. I’m talking about gene therapy, which is developed at the institute. Your Neovasculgen is designed to stimulate vascular growth in a limb in order to replace vessels lost due to severe limb ischaemia. Over the past couple of years, you have been able to reduce the price of Neovasculgen more than two-fold, and now it costs around $1,500 – probably the most affordable gene therapy in the world. It was a hard decision for you of course, as this price can barely recoup what you invested into the research behind it, but it allowed you to have this gene therapy included in the list of essential medicines in Russia, which improves access to it. Can we expect similar breakthroughs in the case of SPRS?

It is necessary to understand that in the case of SPRS therapy, we do not work directly with patients; the final price for the patient is set by the clinics, with which we work in terms of bilateral agreements. Quite often, to our great regret, the final price is triple our production cost (i.е. what we spend to produce the cell culture for one individual patient), and in some clinics, it is quadruple or quintuple! Now, we are trying to work with new clinics to reduce their costs so that we can make this therapy affordable for more people.

In addition to helping people to become younger, you often write in your blog about your personal health strategy. What elements, in your opinion, should be the basis of such a strategy? What methods of slowing aging do you consider to be sufficiently scientifically valid, and what are you personally using?

What happens to us with increasing age? First, an increase in food intake; second, a decrease in motor activity; and third, a decrease in the body’s ability to mobilize fats. Starting at age 30, alas, the fat content in the body begins to increase, but the net body weight – due to the reduction of muscle tissue and demineralization of bone tissue – begins to decrease. It is caused by many factors, not least of which is the same decrease in motor activity due to metabolic processes deteriorating with age. This becomes a vicious cycle. Therefore, the algorithm is very simple.

1) Increased physical activity, which leads to greater energy expenditure. What kind of training is the easiest and most useful? Ordinary walking or, better yet, Nordic walking in the cardiological step (ideally 5-6 km/h with a pulse rate of 120 beats per minute). This is a training in the so-called aerobic zone, i.e. low-intensity and long-term physical activity.

I am an adherent of Nordic walking, which employs up to 85% of the muscles of the body and, in addition, supports energy metabolism, pulmonary ventilation and muscle tone, which plays an important role in preventing the development of ischaemic heart disease. However, since any physical activity should be appropriate for age and health status, it is mandatory to control the pulse (heart rate). To monitor my pulse, distance and speed in real time, I use the Runtastic PRO program installed on my mobile phone. My standard training is to walk for at least 3 times a week for a minimum of 30 to 40 minutes. Incidentally, exercise not only strengthens and increases muscle and bone tissue (and we have neither more nor less than 206 bones and more than 640 muscles), it also stimulates the activity of stem cells that are responsible for maintaining the number of cells inhabiting their tissues.

2) Deliberate diet control. Calorie restriction prolongs life in any organism from yeast to primates, including humans. In 2007, evidence of this phenomenon appeared at the cellular level when American scientists, led by Dr. Sinclair (published in the prestigious scientific journal Cell), discovered the genes SIRT3 and SIRT4. The activation of these genes leads to an increase in the same proteins as the family of sirtuins, which are important regulators of slowing the aging of cells and increasing longevity. In general terms, this is the case. There are “power plants” – mitochondria – in the cytoplasm of our cells. When the calories entering the cell are reduced, relevant signals enter the mitochondria and activate a specific NAMPT gene in them, which leads to an increase in the production of certain molecules (the so-called NAD – the main energy carriers in the cell), which, in turn, activate the SIRT3 and SIRT4 genes. The proteins expressed by these genes lead to an improvement in energy metabolism in the cell, and this, in turn, leads to a slower aging of the cell and prevents apoptosis (premature cell death).

As a result, the body slows down the aging process, the development of age-related diseases is delayed, and, accordingly, the lifespan is increased.

This mechanism is proved by the results of a 25-year study published in Nature Communications in 2014. This study was conducted by a team of scientists from the University of Wisconsin-Madison on rhesus macaques. Macaques on a low-calorie diet had normal body weight, a decrease in the rate of loss of muscle mass (which, as is known, accelerates with age), a significant reduction in the risk of developing diabetes and cardiovascular diseases, and an increased lifespan of 30 years or more, despite the fact that the average life expectancy in captivity for these animals is about 26. Incidentally, Sinclair and colleagues assert that exercise exerts the same effect on the body as a low-calorie diet!

3) And, of course, do not forget about the sauna, unless it is contraindicated for health reasons. A sauna offers relaxation, dilates blood vessels, and may reduce the risk of developing respiratory and cardiovascular diseases, senile dementia and even Alzheimer’s disease!

We often ask researchers what their forecast is regarding medical technologies for addressing aging. Do you think that science will be able to defeat aging and thereby prevent age-dependent diseases? What can we do as a community to make this happen sooner?

I think that someday in the future it will happen. It may not be exactly defeating aging but rather increasing the life expectancy and significantly improving the quality of life. However, a lot has already been done in this respect. Which directions do I find promising? Here they are:

1) Gene therapy. In the laboratory, we have already managed to prolong the life of nematode worms, fruit flies, and mice. In humans, genes responsible for prolonging life have also been identified.

2) Cell therapy. Today, a lot of clinical studies are conducted on the treatment of so-called classical age-related diseases by introducing allogenic mesenchymal stromal cells (MSCs) into the damaged parts of the brain and heart, which significantly improves the condition of patients who have suffered strokes and heart attacks. In 2017, a randomized, blind, placebo-controlled clinical trial was conducted in 30 patients with senility syndrome, who were intravenously injected with allogeneic MSCs from young healthy donors. The results of the study showed a significant improvement in physical health in these patients as well as a decrease in the content of inflammatory biomarkers that are specific to this syndrome.

With the help of cell therapy, good results have also been obtained in the restoration of bones, joints, and skin. At present, many leading laboratories in the world have made considerable progress in studying induced pluripotent cells (iPSCs). These cells are desirable because, on the one hand, they have the properties of embryonic stem cells (ESCs) that make them capable of differentiating into any type of cell in the body, and on the other hand, their use makes it possible to avoid the ethical and other problems associated with ESCs. These cells enable the creation of innovative technologies for autogenous therapy of a wide range of diseases, including, of course, age-related pathologies.

3) Growing and transplanting organs. We have already learned to grow in laboratories not only cartilaginous tissue, skin, and blood vessels but also the ureter, bladder, and other hollow organs. The researchers are also working on the creation of artificial hearts and lungs. In short, the prospects are very bright.

What can we do as a society? Increase education and put a maximum of effort into supporting the progress of science and medicine.

I cannot agree more. Thank you very much for your time, Vadim! We wish you and your wife and research partner Alla good luck in further studies!

Date Posted: January 26, 2018

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Extracellular Vesicles and Aging

Stem cell therapies have been developing and evolving rapidly over the last decade, and extracellular vesicles (EVs) are another innovative approach that researchers are exploring. EVs are being explored for their potential as the basis of new cell therapies, taking the signals generated from various types of stem cells and delivering just those signals, rather than the cells, to the patient.

So what are extracellular vesicles?

EVs are basically membrane-wrapped packages that contain proteins and other molecules and are created and released by cells. Nearby cells intercept these packages and adjust their behavior based on the information contained in the EVs.

Various names have been used to refer to the vesicles being released by healthy cells, including ectosomes, microparticles, and shedding microvesicles. For the purposes of discussion, we will use the term extracellular vesicles (EVs) as a generic term to describe all secreted vesicles.

EVs can broadly be described as either exosomes, microvesicles (MVs) or apoptotic bodies depending on their cellular origin:

	Exosomes	Microvesicles	Apoptotic Bodies
Origin	Endocytic pathway	Plasma membrane	Plasma membrane
Function	Intercellular communication	Intercellular communication	Facilitate phagocytosis
Size	40-120 nm	50-1,000 nm	500-2,000 nm
Contents	Proteins and nucleic acids (mRNA, miRNA and other non-coding RNAs)	Proteins and nucleic acids (mRNA, miRNA and other non-coding RNAs)	Nuclear fractions, cell organelles

Extracellular vesicles have attracted considerable interest in the scientific community due to their role in intercellular communication. It has been known for a long time that cells release vesicles into the extracellular environment during apoptosis. However, the fact that healthy cells also release vesicles into the extracellular environment has only been realized more recently.

A review of extracellular vesicles and aging

Today, we wanted to point out a great review paper discussing the potential of extracellular vesicles and how they could be used to develop new kinds of therapies[1].

It is not hard to imagine that stem cell therapies could evolve to include therapies that use cellular signals without any actual cells being transferred. Indeed, we have seen some studies showing that even cell culture that has had stem cells kept in it retains some beneficial properties that can help facilitate healing.

The clinical data thus far strongly supports that many cell therapies produce beneficial effects via this signaling. Mesenchymal stem cells are a classic example; the cells themselves do not survive in the patient for long, but the signals they give off encourage tissue repair.

Conclusion

It is logical that therapies based on just these signals are the next step forward, though they would not totally replace whole-cell therapies. It is important that we develop efficient ways to transplant stem cells and improve their survival and engraftment rates to deal with organ failure. This will improve with time, and, indeed, progress on this front has been rapid in recent years.

Meanwhile, we can consider the use of extracellular vesicles as yet another string on our bow and an option for therapy in certain cases.

Literature

[1] Robbins, P. D. (2017). Extracellular vesicles and aging. Stem Cell Investigation, 4(12).

Date Posted: January 25, 2018

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TIGIT as a Biomarker for T Cell Senescence and Exhaustion

In a new study, researchers propose that TIGIT is a marker of T cell senescence and exhaustion in the immune system [1]. However, not only is TIGIT just a biomarker, it is also a potential therapeutic target; as the researcher team discovered, lowering levels of TIGIT resulted in the restoration of some lost function in T cell populations that were experiencing high levels of senescence and exhaustion.

Aging is associated with immune dysfunction, especially T-cell defects, which result in increased susceptibility to various diseases. Previous studies showed that T cells from aged mice express multiple inhibitory receptors, providing evidence of the relationship between T-cell exhaustion and T-cell senescence. In this study, we showed that T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), a novel co-inhibitory receptor, was upregulated in CD8+ T cells of elderly adults. Aged TIGIT+ CD8+ T cells expressed high levels of other inhibitory receptors including PD-1 and exhibited features of exhaustion such as downregulation of the key costimulatory receptor CD28, representative intrinsic transcriptional regulation, low production of cytokines, and high susceptibility to apoptosis. Importantly, their functional defects associated with aging were reversed by TIGIT knockdown. CD226 downregulation on aged TIGIT+ CD8+ T cells is likely involved in TIGIT-mediated negative immune suppression. Collectively, our findings indicated that TIGIT acts as a critical immune regulator during aging, providing a strong rationale for targeting TIGIT to improve dysfunction related to immune system aging.

A recipe for disaster

An aged immune system is rife with dysfunction, with too many senescent and exhausted cells causing inflammation and not doing their jobs properly. Many immune cells become specialized to deal with persistent viruses, such as cytomegalovirus, which takes up immune space. This all adds up to a recipe of increasing dysfunction and decline as we age and ultimately leaves us vulnerable to pathogens and infections.

It has been suggested by some researchers that the problem lies with these dysfunctional immune cells and that removing them could be a potential approach to restoring efficient function to the immune system. This would be the same approach as removing senescent cells from any other tissue, and the use of senolytics, drugs that induce cell death in target senescent cells, could also be the solution here.

Another option could be to completely remove the immune system and start over; although while this is currently possible and has been done in some patients undergoing organ transplants, it is a risky procedure and not safe enough to be used in older people. Presently, the method for doing this is to use high doses of immunosuppressive drugs followed by cell therapy to repopulate the immune system. This approach has also been used to treat the autoimmune condition of multiple sclerosis, but the risks are high.

Conclusion

Senescent cells are without a doubt one of the reasons we age, so the discovery of TIGIT as a biomarker is promising. Senescent cells age us by contributing to the background of chronic inflammation known as inflammaging, so their removal is a solid strategy for improving tissue health and preventing diseases.

Now that TIGIT has been identified as a potential therapeutic target, companies like Oisin Biotechnologies could potentially use their programmable gene therapy to attack senescent immune cells. Systems like this also have an advantage over traditional small molecules, as they are faster to configure and deploy against a target gene without the off-target side effects that drugs have.

References

[1] Song, Y., Wang, B., Song, R., Hao, Y., Wang, D., Li, Y., … & Kong, Y. (2017). T‐cell Immunoglobulin and ITIM Domain Contributes to CD8+ T‐cell Immunosenescence. Aging Cell.

Date Posted: January 22, 2018

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Starving Cancer Cells to Death

Novel therapeutic approaches may often require quite a bit of lateral thinking, as researchers at the Salk Institute have recently shown in a study presenting a novel method to interfere with cancer growth.

The problem with cancer

In a nutshell, the reason cancer is such an insidious enemy is that its cells divide uncontrollably, leading to the formation of tumors that keep growing, impair bodily functions, and in a worst-case scenario, metastasize—they spread from their original site, wreaking havoc around the body.

Thus, methods to directly prevent cancer cell division have long been a major research target worldwide. Salk researchers, however, decided to try to intervene a little earlier in the chain of events, messing with cancerous cells’ growth rather than division. To do so, they interfered with cancer’s ability to evade the constraints imposed by the circadian cycle.

What is the circadian cycle?

You can think of the circadian cycle as a sort of internal clock of your body that regulates many different mechanisms. The cycle starts over about every 24 hours (hence the term “circadian”, coming from Latin circa “about” and dies “day”), and among its many functions, it tells cells when they’re supposed to produce and consume nutrients. Healthy cells are normally allowed to do so for about 12 hours a day, in order to prevent them from being overwhelmed by a flood of excessive nutrients.

When cell mealtime is over, levels of the REV-ERB protein rise, which inhibits the cell’s ability to synthesize fats and shuts down autophagy—the cell’s ability to recycle materials, which has implications for longevity and atherosclerosis, for example. When REV-ERB levels go down again, cells resume fat production and start breaking down useless cellular components.

Cancer’s deep appetite

Obviously, in order to keep dividing indefinitely, cancer cells cannot afford the periodic fasting imposed by the circadian rhythm; before they can divide, they need to grow, and in order to grow, they need nutrients. Therefore, furiously paced division requires furiously paced nutrient intake. Hence, all cancers evolve strategies to get around the circadian limitation.

Cancer cells do contain the REV-ERB protein that switches nutrient consumption on and off, but their relevant machinery stays inactive, which allows them to feast all the time and thus grow quickly. This is where Salk researchers intervened.

The team, led by Professor Satchidananda Panda, used two known REV-ERB activators on several different types of cancer cells, including the ill-famed glioblastoma, an extremely dangerous brain cancer. In all cases, the cancer cells, deprived of nutrients, ended up starving to death, whereas healthy cells, which normally undergo this periodic fasting, were unaffected. Tested in a mouse model of glioblastoma, the treatment successfully eliminated cancer cells while seemingly leaving healthy ones alone.

Conclusion

This study may hold the promise of novel anticancer approaches with minimal side effects, if any. However, in order to assess this, follow-up studies will be required to make sure of how exactly REV-ERB activators affect metabolism, particularly the metabolism of the gut microbiome. It should also be noted that this is only one of many possible methods to control cancerous cells’ growth and thus interfere with their ability to proliferate. However, we will follow the development of this research with great interest.

Literature

[1] Sulli, G., Rommel, A., Wang, X., Kolar, M. J., Puca, F., Saghatelian, A., … & Panda, S. (2018). Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature.

Date Posted: January 19, 2018

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Is Aging Natural, a Disease That We Can Treat, or Both?

Aging is something that we all share, rich or poor; it is something that happens to us all, and we are taught from a young age that it is inevitable. However, some scientists believe that aging is amenable to medical intervention and that such interventions could be the solution to preventing or reversing age-related diseases.

Academics are currently debating whether aging is natural or a pathological disease that we can treat.

In fact, there is now pressure from many academics to classify aging itself as a disease; indeed, doing so could potentially improve funding for aging research and help to speed up progress in finding solutions to age-related diseases.[1] The debate continues, but does it really matter if aging is classified as a disease, or is it largely a matter of semantics?

Fighting a losing battle

Current medical practice sees us trying to treat age-related diseases in the same way we do other diseases; this is the “infectious disease model”, and when it comes to treating age-related diseases, it is a losing battle.

The current approach works like this: as soon as a disease appears, the doctor attacks the disease using everything in the medical armory, and the patient can then continue with life until the next disease happens; this process is repeated until failure. This is an excellent way to deal with infectious diseases, and it has helped to increase life expectancy greatly in the last century; however, there are signs are that this approach is starting to run out of steam.[2-4]

Unfortunately, this “whack-a-mole” approach is a poor choice when it comes to treating the chronic diseases of old age. This is because the damage that the aging processes cause still continues to take its toll; therefore, treating the symptoms will ultimately achieve very little and certainly not cure the disease.

So, given that the aging processes lead to the diseases of aging, it is understandable that scientists are starting to consider aging itself to be a disease. While we do not yet fully understand all the intricacies of aging, we already know a great deal about the individual processes.[5] Certainly, we now know enough about aging to begin developing and testing interventions that directly target the underlying processes in order to prevent or treat pathology.

Treating the underlying processes and repairing their damage, which leads to the familiar diseases of old age, is the basis for the medical approach known as rejuvenation biotechnology, a multidisciplinary field that aims to prevent and treat age-related diseases by targeting the aging processes directly.

Aging is the foundation of age-related diseases

Even if aging is not a disease itself, the individual processes do lead to pathology and age-related diseases, such as cancer, heart disease, Parkinson’s, and Alzheimer’s. So, knowing that these processes create the conditions for diseases to develop, it makes sense to target the processes themselves in order to potentially prevent or treat a slew of age-related diseases at once.

The changes that aging brings vary from one person to another, but the common processes of aging are at work in all of us, albeit with some small variances between individuals. For example, we all suffer wear and tear in our joints due to the loss of cartilage, and we all experience the loss of skin elasticity due to the degradation of elastin and the failure of connective tissues. We all encounter other age-related changes, such as the accumulation of non-dividing senescent cells that cause chronic inflammation and disrupt tissue repair, and we also suffer from the accumulation of metabolic waste products that collect in our bodies over time.

As these changes progress, they eventually lead to the familiar diseases of aging. For example, lipids are critical for the function of our metabolism and are essential as part of our diet; however, over time, these processed lipids begin to accumulate in the blood vessel walls. Macrophages arrive to clear the toxic fatty waste away, but they become immobilized and die. This causes inflammation, attracting more macrophages and continuing the cycle. Ultimately, this debris forms plaques that harden the blood vessels and cause them to narrow; this causes blood pressure to rise and can eventually result in a heart attack or stroke.

This demonstrates that the normal metabolic processes that keep us alive ultimately lead to disease. Importantly, in this case, the early age-related changes that set the scene for disease progression, such as high cholesterol, have no symptoms. Nevertheless, such changes are the precursors of deadly diseases and are considered suitable targets for treatment. The same can be said for the other, more subtle, changes and damages that the aging processes cause.

Age-related conditions, such as arthritis, diabetes, osteoporosis, Alzheimer’s, Parkinson’s and many cancers, all follow this dynamic. Simply put, given the sufficient passage of time, the aging processes will cause us to suffer from multiple diseases. Therefore, we should consider these diseases to be the clinical manifestation of these age-related changes. In fact, medicine has been fighting against age-related changes for a long time, even if it was not obvious. For example, a doctor recommending that his patient should reduce his fat and carbohydrate intake to delay heart disease is already fighting those age-related changes. The diabetic who modifies her diet to better manage blood sugar levels is also doing the same thing.

Some people might contest this point of view, stating that the aging process is “natural” and therefore cannot be a disease. The argument that natural things are always good, the appeal to nature, is a logical fallacy. Such people may see natural and pathological as being mutually exclusive. Thus, what is natural must always be good, and what is pathological is bad, and so it cannot also be natural. This is, of course, false when you consider the meaning of each word. Natural simply means something that follows the normal, established course of events, and pathological means something that is harmful.

Conclusion

So, is aging natural or pathological? Well, by the dictionary definitions, aging can be described as both natural and pathological without contradiction.

Additionally, as it is currently classified, aging could be considered a syndrome, specifically a co-morbid syndrome. This really does describe aging perfectly; it is a group of symptoms that consistently occur together and a condition characterized by a set of associated symptoms. Ultimately, aging is an umbrella term describing a range of pathological changes; it may struggle to be accepted as a disease, but it already qualifies as a syndrome.

However, the question of aging being a disease or not is essentially semantic in nature. What rejuvenation biotechnology seeks to achieve is nothing more than preventing age-related diseases by treating the early stages of pathology, which are considered a natural process. While these early age-related changes have not been given a disease name, they are instrumental in the development of diseases, and surely, when it comes to medical treatment, that is all that matters.

References

[1] 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.

[2] Crimmins, E. M. (2015). Lifespan and healthspan: Past, present, and promise. The Gerontologist, 55(6), 901-911.

[3] Olshansky, S. J., Passaro, D. J., Hershow, R. C., Layden, J., Carnes, B. A., Brody, J., … & Ludwig, D. S. (2005). A potential decline in life expectancy in the United States in the 21st century. New England Journal of Medicine, 352(11), 1138-1145.

[4] Reither, E. N., Olshansky, S. J., & Yang, Y. (2011). New forecasting methodology indicates more disease and earlier mortality ahead for today’s younger Americans. Health Affairs, 10-1377.

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

Date Posted: January 18, 2018

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Distinct Types of Amyloid-Beta Prions in Alzheimer’s Found

In a paper in the Proceedings of the National Academy of Sciences, a research team led by Carlo Condello presented their results from a study of the sliced brain fragments of deceased Alzheimer’s disease (AD) patients. It appears different amyloid-beta prions are uniquely associated with different AD variants [1].

A primer on Alzheimer’s disease

AD is a chronic neurodegenerative disease affecting about 5% of the population above 65 years of age—the time when the first symptoms usually manifest. It is estimated to be the cause of up to 70% of all cases of dementia, which according to WHO projections, by 2050 will be around 115 million.

Initial symptoms may be as apparently inconspicuous as forgetting somebody’s name or being easily confused by unfamiliar situations, but eventually, they become more severe, significantly affecting the patient’s cognitive abilities, impairing speech, inducing immotivated anxiety or aggressive behavior, and even delusions. As the disease progresses, patients become unable to perform fine motor tasks, such as dressing, and to take care of themselves. Eventually, patients become bedridden, incapable of feeding themselves or performing even the simplest tasks. Death usually occurs as a consequence of the complications that eventually arise.

Amyloids and the new study

The exact cause of AD is not clear, but different theories have been proposed, suggesting causes ranging from genetic factors to amyloid-beta and tau protein build-up, to reduced synthesis of the neurotransmitter acetylcholine, to a combination of different possible factors.

However, it is established that Alzheimer’s patients show an abnormally high presence of amyloid plaques—misfolded protein aggregates that build up in the patients’ brains—and since 1991, the hypothesis that this excess may be the root cause of the disease has been one of the most prevailing. More precisely, it is thought that the real culprit might be amyloid-beta prions—a type of infectious protein, in the sense that they can induce other, normal protein to misfold in their same way and thus spread and cause disease, somewhat resembling a viral infection.

In the study by Condello’s team, slices from the brains of 41 deceased AD patients were examined. Researchers used fluorescent probes—chemicals that bind to specific molecules and, by their own fluorescence, “highlight” them—to locate amyloids and confocal spectral analysis to analyze the samples. They found that each patient affected by a certain, specific AD variant exhibited only one or two different strains of amyloid-beta prions; this seems to indicate that initial, more stable strains may take over other prion strains and become dominant, potentially explaining the different features of the various diseases in within the Alzheimer’s spectrum.

In their paper, the team stresses the urgency of developing clinical PET probes sensitive enough to detect different prion strains in patients’ brains, which may allow not only earlier detection of AD—and thus grant more time for a therapeutic intervention—but also tailoring treatments to each individual case.

Literature

[1] Condello, C., Lemmin, T., Stöhr, J., Nick, M., Wu, Y., Maxwell, A. M., … & Bird, T. D. (2018). Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer’s disease. Proceedings of the National Academy of Sciences, 201714966.

Date Posted: January 18, 2018

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Could Filtering Our Aged Blood Keep us Young?

There has been a lot of hope and hype around blood transfusions and it being able to reverse aging recently. We decided to take a look at the science behind the idea and talk with a leading expert in the field to see what the reality was.

Is the blood a key to aging?

Due to a recently published study on the effects of young plasma on aged mice, we got in touch with Dr. Irina Conboy of the University of California Berkeley. Dr. Conboy is an Associate Professor at the Department of Bioengineering and an expert in stem cell niche engineering, tissue repair, stem cell aging and rejuvenation. Before we dive into the main topic, let’s familiarize ourselves a little with Dr. Conboy and her work.

Dr. Conboy got her Ph.D. at Stanford University, focusing on autoimmunity. She met her partner in science—and in life—Dr. Michael Conboy at Harvard and they got married before embarking on graduate studies; they celebrated their Silver Anniversary a few years ago. During her postdoctoral studies, she began focusing on muscle stem cells, trying to figure out what directs them to make new healthy tissue and what causes them to lose their ability to regenerate the tissues they reside in as we age [1].

Together with her husband Michael, she eventually discovered that old stem cells could be reactivated and made to behave like young ones if appropriately stimulated. The Conboys’ parabiosis experiments—which consisted in hooking up the circulatory systems of aged and young mice—showed that old age is not set in stone and can be reversed in a matter of weeks [2].

The follow-up work by the Conboys uncovered that age-accumulated proteins, such as TGF-β1, inhibited stem cells’ ability to repair tissues even in young mice, and when TGF-β1 signaling is normalized to its young levels, old mice (equivalent to 80-year old people) have youthful muscle regeneration and better neurogenesis in the hippocampus (the area of the brain that is responsible for memory and learning)[3].

While young blood did appear to be beneficial to old stem cells, their evidence suggested that the real culprit of the broad loss of tissue repair with age was the negative influence of age-accumulated inhibitory proteins in aged tissues and circulation, also called the stem cell niche [4].

The results support that aging is at least partly due to damage accumulation

This conclusion is certainly compatible with the view of aging as a damage accumulation process [5]. As Irina herself pointed out in this interview, in the parabiosis experiments, the old mice had access to the more efficient young organs: lungs, liver, kidneys and immune system of the younger mice, which likely accounted for many of the benefits observed in the elderly parabiosed mice. With respect to the rejuvenation of the brain, the old mice experienced environmental enrichment by being sutured to young, more active parabionts, and this is known to improve the formation of new brain cells, learning, and memory.

An aged niche blocks the action of old and young stem cells alike very quickly; therefore, as Dr. Conboy observed in an article in the Journal of Cell Biology, we can’t treat the diseases of aging by simply transplanting more stem cells, because they will just stop working. Their niche needs to be appropriately engineered as well. Fortunately, there are potential solutions to this problem; such as the use of artificial gel niches and defined pharmacology that are designed to protect transplanted or endogenous stem cells from the deleterious environment of the old body.

This research holds the potential to significantly postpone the onset of age-related diseases and possibly reverse them one day, including frailty, muscle wasting, cognitive decline, liver adiposity and metabolic failure, but Dr. Conboy remains cautious about the possibilities until more data is in. However, she does think that longer and healthier productive lives could improve people’s attitudes towards the environment and treating each other with compassion and respect—a view that we definitely share.

We managed to catch up with Irina and Michael Conboy and talk to them about their work.

For the sake of those new to the topic, what is it in young blood and aged blood that affects aging?

Irina: Numerous changes in the levels of proteins that together regulate cell and tissue metabolism throughout the body.

Mike: We wondered why almost every tissue and organ in the body age together and at a similar rate, and from the parabiosis and blood exchange work now think that young blood has several positive factors, and old blood accumulates several negative, “pro-aging” factors.

A lot of media attention and funding is currently being directed to youthful blood transfusions; how can we move beyond this to potentially more promising approaches, such as filtering and calibration of aged blood?

Irina: People need to understand not just the titles, abstracts and popular highlights of research papers, but the results and whether they support (or not) the promise of rejuvenation by young blood. In contrast to vampire stories, we have no strong experimental evidence that this is true, and there is a lot of evidence that infusing your body with someone else’s blood has severe side effects (even if it is cell-free).

Mike: Translational research!

Some evidence suggests dilution is the most likely reason that young blood has some beneficial effects; what are your thoughts on this recent study[6] in rats that shows improved hepatic function partially via the restoration of autophagy?

Irina: There are certainly “young” blood factors that are beneficial, not just a dilution of the old blood, and this benefit differs from organ to organ. We have published on improved liver regeneration, reduced fibrosis and adiposity by transfusion of old mice with young blood, but these are genetically matched animals, and in people, we do not have our own identical but much younger twins[7].

If dilution is also playing a role here, then can we expect similar or better results from calibrating aged blood?

Irina: Yes, and our work in progress supports the idea.

In your 2015 paper, you identified that TGF-β1 can be either pro-youthful or pro-aging in nature, depending on its level[8]. In the study, you periodically used an Alk-5 inhibitor to reduce TGF-β1 levels and promote regeneration in various tissues. In the study, you showed that TGF-β1 was important in myogenesis and neurogenesis; is there reason to believe that this mechanism might be ubiquitous in all tissues?

Irina: Yes, because TGF-β1 receptors are present in most cells and tissues.

Also, TGF-β1 is only one of a number of factors that need to be carefully balanced in order to create a pro-youthful signalling environment. How many factors do you believe we will need to calibrate?

Irina: There will be a certain benefit from calibrating just TGF-beta 1, but also additional benefits from more than one or just TGF-beta.

How do you propose to balance this cocktail of factors in aged blood to promote a youthful tissue environment?

Irina: We are working on the NextGen blood apheresis devices to accomplish this.

So, you are adapting the plasmapheresis process to effectively “scrub” aged blood clean and then return it to the patient. This would remove the need to transfuse blood from young people, as your own blood could be filtered and returned to you, and no immune reaction either, right?

Irina: Accurate.

This plasmapheresis technique is already approved by the FDA, we believe, so this should help you to develop your project faster, right?

Irina: Exactly.

Do you think a small molecule approach is a viable and, more importantly, a logistically practical approach to calibrate all these factors compared to filtering aged blood?

Irina: Yes, it is a very feasible alternative to the NextGen apheresis that we are working and publishing on.

It is thought that altered signaling is caused by other aging hallmarks higher up in the chain of events; even if we can “scrub” aged blood clean, is it likely to have a long-lasting effect, or would the factors reach pro-aging levels fairly quickly again if nothing is done about the other hallmarks antagonizing them?

Irina: That needs to be established experimentally, but due to the many feedback loops at the levels of proteins, genes and epigenetics, the acquired youthful state might persist.

Ultimately, could a wearable or an implanted device that constantly filters the blood be the solution to these quickly accumulating factors?

Irina: Maybe, but the first step of a day at a NextGen apheresis clinic once every few months might be more realistic.

Filtering seems to be a far more practical solution, so how are you progressing on the road to clinical trials?

Irina: We are collaborating with Dr. Dobri Kiprov, who is a practicing blood apheresis physician with 35 years of experience, and he is interested in repositioning this treatment for alleviating age-related illnesses.

Senolytics and removing senescent cells and the resulting inflammation they cause during the aging process has become a hot topic in the last year or so. What are your thoughts on senolytics as a potential co-therapy with a blood filtering approach?

Irina: Might be good, but we should be careful, as p16 is a normal, good gene that is needed for many productive activities by many cells.

What do you think it will take for the government to fully support the push to develop rejuvenation biotechnology?

Irina: Clear understanding of the current progress and separating the real science from snake oil is very important for guiding funding toward realistic clinical translation and away from the myth and hype.

The field is making amazing progress, but, sadly, it is plagued by snake oil. As much as an “anti-aging free market” encourages innovation, it also encourages hucksters. How can a member of the public tell the difference between credible science and snake oil?

Irina: I was thinking for some time about starting a popularized journal club webpage where ordinary people can see what we typically critically point out in the lab setting about published papers and clinical trials.

How can our readers learn more about your work and support your research?

Irina: The new Conboy lab website is coming up; meanwhile, contact me and Dr. Mike at iconboy@berkeley.edu and conboymj@berkeley.edu

Conclusion

We would like to thank Irina and Michael for taking the time to answer our questions and for providing the readers with a fascinating insight into their work.

Literature

[1] Conboy, I. M., Conboy, M. J., Smythe, G. M., & Rando, T. A. (2003). Notch-mediated restoration of regenerative potential to aged muscle. Science, 302(5650), 1575-1577.

[2] Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433(7027), 760-764.

[3] Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L., Paliwal, P., … & Schaffer, D. (2015). Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget, 6(14), 11959.

[4] Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature communications, 7.

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

[6] Liu, A., Guo, E., Yang, J., Yang, Y., Liu, S., Jiang, X., … & Gewirtz, D. A. (2017). Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy. Aging cell.

[7] Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature communications, 7.

[8] Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L., Paliwal, P., … & Schaffer, D. (2015). Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget, 6(14), 11959.

Date Posted: January 10, 2018

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World Health Organization Puts the Elderly Back in the Picture

Not long ago, we wrote about some complications involving the WHO 13th programme of work. In the initial version of this document, developed by the WHO working group in November 2017, the problems of the elderly were nearly completely overlooked. The joint efforts of our community helped to bring this critical flaw to public attention.

During the meeting of the working group, it was announced that 90% of the comments received by WHO (out of 400) pointed out the need to set healthy aging as one of the priorities of the new programme of work. However, we didn’t know if our demand to focus on the implementation of the global strategy and action plan on aging and health would be fulfilled.

The good news is that the new draft programme published on the WHO site on January 5th (the draft was removed from WHO site some time after this article and incorporated into the 13th program of work) includes several provisions related to aging. Our community managed to persuade these global policymakers to implement the activities listed in the global strategy to help society prepare for the Decade of Healthy Aging (2020-2030). Let’s have a closer look at these provisions.

15. The foundation of WHO’s work is SDG 3: ensuring healthy lives and promoting well-being for all at all ages. WHO is an organization focused principally on promoting health rather than merely fighting disease, and especially on improving health among vulnerable populations and reducing inequities. Leaving no-one behind, the Organization aims to give women and men, girls and boys, in all social groups, the opportunity to live not just long but also healthy lives. WHO will explore measuring this foundation of its work using healthy life expectancy, which could serve as one overarching measure aligned with SDG 3, complemented by the triple billion goal, which leads to three more specific priorities, each with overlapping one-billion people goals.

Healthy life expectancy (HALE) is an assessment of the period of time that a person can live in full health. HALE is usually lower than total life expectancy, and the difference between HALE and total life expectancy is regarded as years of life lost to disease.

As the goal of our community is to prolong the healthy period of life by addressing the root mechanisms of aging and postponing age-related disease, the introduction of HALE as a way to measure WHO activities is a very good outcome. It is very hard to preserve health in older ages without addressing the underlying mechanisms of aging and implementing an extensive program that involves educating the public about healthy lifestyles. This choice of indicator means that WHO will strengthen its efforts to keep people healthy for as long as possible, which will ease the introduction of rejuvenation interventions once they are available, as it will likely be a cost-effective way to achieve a more favorable HALE.

16. Life expectancy at birth has consistently increased since the 19th century, largely due to socioeconomic developments and public health measures such as vaccination, nutrition and sanitation. Today, socioeconomic, political, cultural, environmental and economic forces continue to drive changes in the burden of disease. However, efforts are needed to ensure that their impact is positive. Poor health literacy coupled with weak health-promoting policies make it difficult for people to make healthy choices for themselves and their families. Investment in health promotion and disease prevention allows countries to address economic concerns about the rising costs of the health system and enables potential savings if disease can be avoided.

The WHO draft programme of work refers here to the increasing burden of chronic, non-communicable diseases due to the increasing proportion of people age 60 and over. Indeed, it would be really hard to double or even triple healthcare and pension expenditures for many countries, especially taking into account the ongoing economic crisis. However, this is what aging societies will have to do if HALE does not grow faster.

This is why WHO is only promoting evidence-based interventions that represent the “best buy” scenarios: the most realistic and cost-effective. When it comes to age-related diseases, which can last 20-30 years or longer, prevention could be much cheaper, and it is more humane, as this scenario would reduce unnecessary human suffering. Therefore, we could consider this provision of the new draft programme as supporting our efforts to introduce longevity lifestyles and even “soft” (careful and evidence-based) biohacking.

17. Healthy life expectancy has not increased at the same pace as life expectancy, and increasing age often brings increasing morbidity and reduced functioning, making healthy ageing an important focus. Most disability-adjusted life years in older age are attributable to chronic conditions and the accumulated impact of such conditions can lead to significant loss in function and care dependence in older age. At the same time, there is emerging evidence that healthy ageing depends on early childhood development and is epigenetically determined. Ensuring healthy ageing is an urgent challenge in all countries.

This provision once again underlines how important it is to focus on prevention. I would like to point out that if childhood is perceived as the foundation of healthy lifestyles, longevity advocates receive carte blanche for working with the younger generation. Activists could think of developing corresponding education programs for schools and universities, and this very provision can be a strong argument when offering such a program to educational authorities.

37. Ensuring healthy ageing is central to universal health coverage, just as it is to the other priorities of GPW 13. The number of people over the age of 60 is expected to double by 2050 and this unprecedented demographic transition will require a radical societal response. The Secretariat will support Member States to promote healthy ageing through the actions defined by the Global strategy and action plan on ageing and health (2016), as well as through the Decade of Healthy Ageing that is planned for the period 2020−2030. These actions include aligning health systems to the needs of older populations, with a special focus on enhancing the functioning of older persons and the management of chronic disease; improving access to medicines; developing systems of longterm care including community-based services; promoting palliative care, creating age-friendly environments; and improving measurement, monitoring and understanding of healthy ageing.

This provision is exactly what we were aiming for when calling the members of our community to take part in the Open Consultation or the Draft. As you remember, all mentions of the WHO documents related to aging were absent; this provision clearly shows that we achieved our goal! Even though the global strategy and action plan on aging and health may not be ideal in terms of rejuvenation research promotion, it helps member states navigate the field with more confidence. This global strategy, which we wanted so much to be the foundation of the draft programme provisions related to aging, contains a very important paragraph that every activist should know about:

105. Finally, better clinical research is urgently needed on the etiology of, and treatments for, the key health conditions of older age, including musculoskeletal and sensory impairments, cardiovascular disease and risk factors such as hypertension and diabetes, mental disorders, dementia and cognitive declines, cancer, and geriatric syndromes such as frailty. This must include much better consideration of the specific physiological differences of older men and women and the high likelihood that they will be experiencing mutimorbidities. This could also be extended to include possible interventions to modify the underlying physiological and psychological changes associated with ageing.

Conclusion

Dear friends, this is a victory! Our community managed to influence policymakers at the highest level: the World Health Organization. We managed to ensure that the new programme of work considers aging and age-related diseases to be an important issue, and the resulting global strategy and action plan on aging and health is an effective guide to helping our society adapt to population aging.

In terms of advocacy, this is a complete victory, which shows two important things. First, when we join forces, we can influence global health policy at the highest level. Our community became stronger, and our voice is being heard! Second, this victory shows that dialogue with the UN and its institutions, including decision-makers in these agencies, is possible, and it goes in the directions that we need: more focus on prevention and more focus on public health education related to aging,

I offer special thanks to Dr. Ilia Stambler for initially turning the attention of the community to this issue. I want to thank and congratulate all participants in the Open Consultation with this achievement. Of course, we are still at the beginning of our path to rejuvenation as a public health priority, but outcomes like this one make me believe that there are more victories to come. Let’s keep working, as the main reward is worth it: health, youth, and freedom from age-related diseases for all!

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Building a Future Free of Age-Related Disease