Fight Aging! Newsletter, June 27th 2016

June 27th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • A So Far Weak Approach to Stimulating Autophagy to Slow Aging
  • Recent Research on Exercise, Aging, and Age-Related Disease
  • Crowdfunding Longevity Science: an Interview with Keith Comito of
  • Rejuvenation Biotechnology 2016 will be Held at the Buck Institute in California
  • If I Were Going to Raise a Venture Fund, I'd Earmark 10% of Capital for Creating Startups By Funding Research that is Close to Completion
  • Latest Headlines from Fight Aging!
    • In Search of Early, Asymptomatic Stages of Alzheimer's Disease
    • Suggesting that Higher Levels of IGF-1 Might Slow Atherosclerosis Progression
    • Investigating CD38 and NAD in Aging
    • Another Possible Cancer Suppression Mechanism in Naked Mole Rats
    • 7-ketocholesterol Accumulation Speeds Calcification of Blood Vessels
    • Chimeric Antigen Receptor Cancer Therapies Can Now Target Solid Tumors
    • Mitofusin 2 in the Development of Sarcopenia
    • Diabetes Greatly Increases Risk of Heart Attack
    • Exploring the Mechanisms of Age-Related Slowing of Visual Perception
    • The Biochemistry of Mammalian Hibernation as a Possible Basis for Therapies


The research materials for today offer one example of numerous parallel efforts to find a mechanism and drug candidate that can stimulate autophagy and thereby modestly slow the progression of aging. It is too early to say whether this particular mechanism is worth chasing for that part of the drug development research and development industry that sees potential in slightly slowing aging, but the initial demonstration isn't impressive. It extends mean life span in flies by about 5%, which is small enough that no-one should be holding his or her breath expecting a clear and clean replication of the results. Certainty in manipulation of the pace of aging tends to require larger gains in order for clarity to emerge across numerous studies by different research groups. Results in short-lived species like flies are rarely within a 10% of life span distance of one another from study to study and research group to research group. Statistics and chance are cruel mistresses both. It is also good to remember that short-lived species have much more plastic life spans than long-lived species. Some of the changes that extend life in flies by 30% or so do also produce benefits to health in humans, but none have such an obvious effect on life span in our species.

Autophagy is a collection of cellular housekeeping mechanisms responsible for identifying, sequestering, and removing damaged structures and proteins. The damage is contained, broken down, and the parts recycled. The more of this that takes place, the more pristine the cell, and the less time that a damaged component has to cause further problems. Many of the methods of modestly extending life in short-lived species feature enhanced autophagy, and some actually require the correct operation of autophagy in order to slow aging. Given the importance of mitochondrial damage in aging, it is reasonable to think that a large part of this results from better quality control of mitochondria. Proving which aspect of autophagy is more or less important is ever a challenge, however, as is the case for any effort to isolate just one process in the dynamic chaos of cellular biochemistry in a living individual. Everything influences everything else.

For more than a decade now, researchers been earnestly looking for drugs that can enhance autophagy to a large enough degree to make deployment as a therapy worthwhile. Some technology demonstrations suggest that there are ways to enhance autophagy greatly, and restore youthful function in at least some types of aged tissues as a result. Genetic engineering to add extra lysosomal receptors springs to mind, given its restoration of liver function in old mice. Lysosomes are the destination for structures and molecules flagged for recycling, and play an important role in the process of autophagy. Drug candidates mined from the existing catalogs are vanishingly unlikely to achieve an outcome of this magnitude, however. Given that slowed aging produced by calorie restriction has been shown to depend on autophagy to a large degree, there is the hope in some quarters that autophagy enhancement may be a path to effective calorie restriction mimetic drugs. Again, modestly slowing aging is the goal in this research.

For my part I believe that most attempts to find methods of autophagy enhancement are not useful approaches to treating aging, especially the standard drug discovery efforts. The expected gains are too small, a mere slowing of aging, in comparison to the rejuvenation that might be achieved through the repair approach espoused in the SENS research initiative. Aging is damage: researchers should be aiming to repair that damage, not to slow down its accumulation. Autophagy just isn't comprehensive enough or effective enough for this job. The types of therapy needed to repair the root cause cell and tissue damage that produces degenerative aging are no more expensive or time-consuming to develop than therapies to slow aging, but have the potential to produce rejuvenation - a much better class of outcome, a treatment that can be repeated over and again to keep producing benefits for any one individual. Unfortunately, repair as a strategy and rejuvenation as a goal is still a minority concern within the research community. Taking over the mainstream continues to be a matter of bootstrapping support, funding, and results, one small advance at a time. There is progress, certainly, and much more so in recent years, but never fast enough for my liking. The mainstream of the research community has only comparatively recently adopted the idea that aging can and should be treated as a medical condition. Most are still very fixated on the approach of altering metabolism to slightly slow aging: more radical approaches are taking time to win adoption. Time is, of course, is running out of the bottom of the hourglass for all of us, day by day. Strategy in aging research is an urgent matter precisely because this is the case. We can't aim low.

Ethanolamine: A novel anti-aging agent

Phosphatidylethanolamine (PE) is a central intermediate of lipid metabolism and a major component of biological membranes. Within cellular membranes, PE not only serves as a structural phospholipid but also regulates the tethering of proteins and fusion processes. Importantly, PE is also directly involved in the process of macroautophagy (hereafter termed autophagy), a lysosome-dependent cellular recycling mechanism that protects cells against lethal stress and extends longevity in model organisms. During autophagy, double-membraned structures that are highly abundant in PE engulf superfluous, supernumerary, or dysfunctional macromolecules or organelles contained in the cytoplasm, forming vesicles (autophagosomes). These autophagosomes then fuse with lysosomes to generate autophagolysosomes in which the luminal cargo is degraded.

Given the widespread functions of PE as a precursor of several biosynthetic pathways, there is high demand for this metabolite. A common PE pool feeds into all major cellular PE-consuming pathways, thus resulting in competition for PE between pathways. As we have recently shown, this limitation can be overcome by genetic or pharmacological interventions. External administration of ethanolamine (Etn), a precursor of PE can increase the abundance of intracellular PE. Supporting a crucial regulatory role for PE in autophagy, we observed that both external supply of PE and an increase in its internal generation similarly increased autophagic flux. Importantly, pharmacological Etn treatment extended the lifespan of yeast and fruit flies, as well as cultured mammalian cells, underlining the potential of Etn as a potent autophagy and longevity drug.

Phosphatidylethanolamine positively regulates autophagy and longevity

Autophagy is regarded as one of the major cytoprotective mechanisms during ageing, and thus is a crucial process to counteract age-associated pathologies. Age-associated neurodegenerative disorders including Alzheimer's and Parkinson's disease may be postponed or attenuated by chronic induction of autophagy, and there is substantial evidence that genetic or pharmacological induction of autophagy can increase the healthspan and lifespan of multiple model organisms including yeast, worms, flies and mice. These findings have spurred the interest in identifying novel, non-toxic pharmacological inducers of autophagy. So far, several agents have been shown to induce autophagy and increase lifespan across several species, namely rapamycin, resveratrol and spermidine. The present results suggest that ethanolamine might be yet another potent autophagy inducer that promotes longevity.

Our study provides evidence that ethanolamine-mediated autophagy induction correlates with enhanced longevity in yeast and mammalian cell culture. This is in line with a previous study in yeast demonstrating that PE is a limiting factor for autophagy. Our results demonstrate that these observations are applicable to a wild-type scenario in yeast too and can be extended to mammalian cell cultures. Still, future experiments will need to clarify if ethanolamine-induced autophagy is beneficial to higher organisms. We could indeed observe a statistically significant increase in the mean lifespan of flies upon supplementation with ethanolamine, but whether this is because of autophagy must be tackled in the follow-up studies.


Quite a lot of research on exercise in the context of aging and age-related disease has been published in the past few months. More than usual, I think - not just a case of noticing because it is on my mind. Research moves in waves and cycles, just like all other human endeavors. Below you will find links to a selection of these items, those that caught my attention as they passed by.

Along with donating to the SENS Research Foundation and the practice of calorie restriction, regular moderate exercise is just about the best thing you can do for your long term health here and now. Both calorie restriction and exercise have been shown to slow aging to a modest degree in animal studies, and the human data is pretty compelling. It is fair to say that exercise produces greater benefits for a basically healthy individual than any presently available medical technology. It even produces better results than the available therapies for a number of age-related conditions. It is all a matter of degrees, however. That I can say this about exercise is less a glowing recommendation for working out and more a dismal review of medicine as it exists in clinical practice today. The research and development community can and will do better, and I don't think that exercise and calorie restriction will go unbeaten by therapies and enhancements for another decade at this point, but it is still frustrating to be in the midst of such a revolutionary period in life science research, yet to reap the harvest of that progress. We don't want medicine that just slows the inevitable a little, we want the inevitable defeated, removed, cured.

A sizable fraction of the aging research community is interested in mimicking the effects of calorie restriction on health and longevity, using drug discovery to find ways to tinker with the same switches in our biochemistry. The same is true of exercise, though researchers in that case are some years behind on the same path, with some catching up to do. While I'm definitely in favor of taking advantage of exercise, as it is here and it is free, and that is a cost-benefit equation hard to argue with, I'm much less enthusiastic about the panoply of approaches that aim to produce much the same outcome via drugs, some way to modestly slow the progression of degenerative aging by taking a pill or undergoing some form of enhancement such as gene therapy. I think the cost to achieve that goal though, for example, standard issue drug discovery and development is unfavorably high, given the very modest scope of the benefits expected to result. If that was all that could be done, then so be it, but it isn't. There are other alternatives, such as the SENS portfolio of research and development based on repair of the cell and tissue damage that causes aging, that have the potential to achieve rejuvenation rather than slowing of aging, and thus produce far greater benefits to health and longevity.

Exercise may have therapeutic potential for expediting muscle repair in older populations

For many mammals, including humans, the speed of muscle repair slows as they grow older, and it was once thought that complete repair could not be achieved after a certain age. This report shows, however, that after only eight weeks of exercise, old mice experienced faster muscle repair and regained more muscle mass than those of the same age that had not exercised. This is important, as it further highlights exercise's therapeutic potential. To make this discovery, researchers used three groups of mice: old mice that were exercise trained, old mice that were not exercise trained, and young mice that were not exercised trained. In the first group, old mice were trained three days/week for eight weeks. The effect of exercise in aging muscle was measured by comparing the three groups of mice. "This is a clean demonstration that the physiological and metabolic benefits of exercise radiate to skeletal muscle satellite cells, the adult stem cells responsible for repair after injury, even in senescent animals. Strikingly, even as the contractile elements of muscle tissue wane with age, the capacity of the satellite cells to respond to exercise cues is maintained. This aging-resistant retentive property could be added to the list of features that define adult stem cells."

Exercise associated with longer life in patients with heart failure

To conduct the study, the investigators identified 23 randomised trials of exercise that included at least 50 heart failure patients who were followed up for six months or longer. After asking the authors of all 23 studies for individual patient data, they received the information from 20 trials. The 20 trials included 4043 patients with heart failure. The investigators used the individual patient data to assess the impact of exercise on the time to all-cause mortality and first hospitalisation. The investigators found that exercise was associated with an 18% lower risk of all-cause mortality and an 11% reduced risk of hospitalisation compared with no exercise. "This analysis did in fact show that there is a mortality benefit from doing exercise. In other words, patients who exercised had a lower risk of death than those who didn't. Patients with heart failure should not be scared of exercise damaging them or killing them. The message for heart failure patients is clear. Exercise is good for you, it will make you feel better, and it could potentially make you live longer."

Run for Your Life: Exercise Protects against Cancer

Exercise may decrease cancer incidence and slow the growth rate of tumors. That's the conclusion of a mouse-based study, reporting that training mice regularly on a wheel decreased the growth of multiple types of tumors, including skin, liver, and lung cancers. Furthermore, mice that exercised regularly had a smaller chance of developing cancer in the first place. The beneficial effects of running went beyond tumor formation and growth, extending to cancer-associated weight loss, a process termed cachexia that is seen in cancer patients. Mice that exercised regularly showed no signs of cancer-associated weight loss in the researchers' lung cancer mouse model.

The researchers say they identified several factors behind the anti-tumor effects of exercise. These anti-cancer effects are linked to the release of adrenaline (also called epinephrine), a hormone that is central to the "fight-or-flight" response. Adrenaline production is known to be stimulated by exercise. The researchers say that, the production of adrenaline results in a mobilization of immune cells, specifically one type of immune cell called a Natural Killer (NK) cell, to patrol the body. These NK cells are recruited to the site of the tumor by the protein IL-6, secreted by active muscles. The NK cells can then infiltrate the tumor, slowing or completely preventing its growth. Importantly, the researchers note that injecting the mice with either adrenaline or IL-6 without the exercise proved insufficient to inhibit cancer development, underlining the importance of the effects derived only from regular exercise in the mice.

Midlife fitness is linked to lower stroke risks later in life

In a prospective observational study consisting of 19,815 adults ages 45 to 50, (79 percent men, 90 percent Caucasian) researchers measured participants' heart and lung exercise capacity and categorized them as having either a high, middle or low level of fitness. The study found that those with the highest level of fitness had a 37 percent lower risk of stroke after age 65, compared to their counterparts with the lowest level of fitness. This inverse relationship between fitness and stroke risks existed even after researchers considered stroke risk factors: high blood pressure, type 2 diabetes and atrial fibrillation. The study reinforces the benefits of being physically fit throughout life. "Low fitness is generally ignored as an actual risk factor in clinical practice. Our research suggests that low fitness in midlife is an additional risk to target and help prevent stroke later in life."


Keith Comito leads the volunteers of the non-profit Life Extension Advocacy Foundation (LEAF) and the crowdfunding initiative, a site I'm sure you've seen at least in passing by now. The LEAF crew have put in a lot of effort to help make fundraisers for rejuvenation research projects a success both last year and this year. Two such crowdfunding campaigns are running right now, firstly senolytic drug research at the Major Mouse Testing Program with just a few days left to go, and in its stretch goals, and secondly the recently launched drug discovery for ALT cancers at the SENS Research Foundation. Both tie in to the SENS portfolio of research programs aimed at effective treatment of aging and all age-related conditions. These are large projects when taken as a whole, but the way forward in this as in all things is to pick out smaller, achievable goals, and set out to get them done. Then repeat as necessary.

I recently had the chance to ask Keith Comito a few questions about, the state of funding for the interesting end of longevity science, and what he envisages for the years ahead. This is an interesting, revolutionary time for the life sciences, in which progress in biotechnology has made early stage research very cheap. A great deal can be accomplished at the cutting edge of medical science given access to an established lab, administrators who can break out small initiatives from the larger goals, smart young researchers, and a few tens of thousands of in funding. It is an age in which we can all help to advance the research we care about, by collaborating and donating, and it has never been easier to just reach out and talk to the scientists involved. If you haven't taken a look at and donated to one of the projects there, then you really should. This is a way to move the needle on aging research, and advance that much closer to effective treatments for the causes of aging.

What is the story in brief? What was the spur that made you come together and decide to do your part in the fight against aging? began to take shape at the tail end of 2012, as a result of a loose discussion group based in New York which consisted of citizen scientists such as myself and Dr. Oliver Medvedik, supporters of SENS, as well as a few healthcare practitioners. We began having monthly meetings to discuss what could be done to accelerate longevity research (usually in oddball locations like salad bars or subterranean Japanese restaurants befitting our motley crew) and eventually hit upon the idea of crowdfunding. What drew us to this idea was that it was something tangible: a concrete way to move the needle on important research not only through funds, but through raised awareness. It is fine to talk and rabble-rouse about longevity, but we felt such efforts would be much more effective if they were paired with a clear and consistent call to action - a path to walk the walk, so to speak. As this idea coalesced we formed the nonprofit LEAF to support this initiative, and the rest is history. Not every one from the initial discussions in 2012 remained throughout the intervening years, but we are thankful to all who gave us ideas in those early days of the movement.

I'd like to hear your take on why we have to advocate and raise funds at all - why the whole world isn't rising up in support of treatments for the causes of aging.

The reasons why people and society at large have not prioritized anti-aging research thus far are myriad: fear of radical change, a history of failed attempts making it seem like a fools errand, long timescales making it a difficult issue for election-focused politicians to support, etc. The reason I find most personally interesting relates to cognitive bias - specifically the fact that our built-in mental hardware is ill-equipped to handle questions like "do you want to live 100 more years?" If instead you ask the questions "Do you want to be alive tomorrow?" and "Given that your health and that of your loved ones remains the same, do you suspect your answer to the first question will change tomorrow?", the answers tend to be more positive.

This leads me to conclude that the state of affairs is not necessarily as depressing for our cause as it might appear, and that reframing the issue of healthy life extension in a way that will inspire and unite the broader populace is possible. Aubrey de Grey has spoken about "Longevity Escape Velocity" in relation to the bootstrapping of biomedical research, but I think the same idea applies to the public perception of life extension as well. The sooner we can galvanize the public to support therapies that yield positive results the easier it will become to invite others to join in this great work. It is all about jump starting the positive feedback loop, and that is why we believe rallying the crowd behind critical research and trumpeting these successes publicly is so vitally important.

What the future plans for and the Life Extension Advocacy Foundation?

In addition to scaling up our ability to run successful campaigns on, we look forward to improving our infrastructure at LEAF by bringing on some staff members to join the team. LEAF has largely been a volunteer effort thus far, and having the support of a staff will allow us to take on more campaigns as well as further improve the workflow to create and promote them. This will also free me up personally to more actively pursue potential grand slams for the movement, such as collaborations with prominent YouTube science channels to engage the public and policy related goals like the inclusion of a more useful classification of aging in the ICD-11.

Do you have any favored areas in research at the moment? Is there any particular field for which you'd like to see researchers approaching you for collaboration?

Senolytics is certainly an exciting area of research right now (congratulations Major Mouse Testing Program!), and a combination of successful senolytics with stem cell therapies could be a potential game changer. That being said I'd also like to see projects which address the truly core mechanics of aging, such as how damage is aggregated during stem cell division, and the potential differences in this process between somatic and germ cells. How can the germ line renew itself for essentially infinity? The real mystery here is not that we grow old, but how we are born young.

A related question: where do you see aging and longevity research going over the next few years?

In the near future we will likely continue to see the pursuit of compounds which restore bodily systems failing with age to a more youthful state. This will include validating in higher organisms molecules that have shown this sort of promise: rapamycin, metformin, IL-33 for Alzheimer's, etc. This approach may sound incremental, but it actually signals a great paradigm shift from the old system of mostly ineffective "preventative measures" such as antioxidants. Things like nicotinamide mononucleotide (NMN), IL-33 - if successful these types of therapies can be applied when you are old, and help restore your bodily systems to youthful levels. That would be a pretty big deal.

Funding is ever the battle in the sciences, and especially for aging. Obviously you have strong opinions on this topic. How can we change this situation for the better?

I believe the key to greater funding, both from public and private sources, is to build up an authentic and powerful grassroots movement in support of healthy life extension. Not only can such a movement raise funds directly, but it also communicates to businesses and governments that this is an issue worth supporting. An instructive example to look at here is the work of Mary Lasker and Sydney Farber to bring about the "War on Cancer". Through galvanizing the public with efforts such as the "Jimmy Fund", they effected social and political change on the issue, and helped turn cancer from a pariah disease into a national priority. If we all work together to build an inclusive and action-orientated movement, we can do the same.


Rejuvenation Biotechnology 2016 is the latest in a series of conferences hosted by the SENS Research Foundation, focused on bringing together industry and academia to pave the way for the advent of first generation rejuvenation therapies. The first of these therapies are already in clinical development, each narrowly focused on one cause of aging, such as senescent cell clearance at Oisin Biotechnologies and some of the SENS Research Foundation's own drug candidates for breaking down damaging metabolic waste at Human Rejuvenation Technologies. There are numerous other examples I could give, for either work based on the SENS vision of controlling aging through repair of cell and tissue damage, or other initiatives with less ambitious goals. If all goes well, they will be available in clinics outside the US within a few years, and have passed through the regulatory system inside the US at most a decade from now.

Building a whole new field of medicine and getting it into the clinic doesn't just magically occur, however. This is a big deal, and requires allies, advocacy, setting expectations, and either pulling in the heavyweight support of Big Pharma or creating an entirely new network of distribution and validation akin to the medical tourism industry for stem cell therapies. Laying these foundations for the work that lies ahead is one of the goals of the Rejuvenation Biotechnology conferences. You can look back in the Fight Aging! archives to read about the 2014 and 2015 conferences; well attended and well spoken of. You might take a look at this year's program for a sense of how the theme will follow on from prior years. Rejuvenation Biotechnology 2016 is being held at the Buck Institute for Research on Aging just North of the Bay Area, California. It is invitation only, I'm afraid - the wages of success and popularity - so if you feel the need to attend, you should contact the SENS Research Foundation folk and ask. The conference will be streamed live this year, however, so no-one need miss out.

Rejuvenation Biotechnology 2016, August 16-17

World populations are aging, and the social and economic burdens of age-related disease are rising steeply. For an increasing number of elderly individuals, healthcare is too often reduced to crisis management in the emergency room, painfully harsh treatments for diseases such as cancer, or best efforts at palliative care.

SENS Research Foundation exists to end aging. Since 2009 we have worked to make the concept of rejuvenation biotechnology - the repairing of the damage which occurs to our bodies as we age - into a reality. Our research, education and awareness programs have created the foundations of the Rejuvenation Biotechnology Industry, an industry that will be capable of targeting the diseases of aging with genuine, effective, affordable cures.

The 2016 Rejuvenation Biotechnology Conference is focused on taking the Rejuvenation Biotechnology Industry to the next level by addressing the question: what will it take to push emerging breakthroughs in regenerative medicine from proof-of-concept to implementation? This year's conference seeks to answer this critical inquiry by covering all the stages from securing funding, to production, to navigating regulation, to clinical evaluation and adoption of new treatments. Industry-leading experts will present real-life examples drawn from their own work followed by an open panel discussion and Q&A. As with our previous conferences, we provide ample time for networking with industry leaders, funders and researchers.

Due to our limited space the 2016 Rejuvenation Biotechnology Conference is an invitation-only event. In order for our entire community to be able to participate we will be live streaming the conference and everyone is invited to join us via the live stream. To stay in the loop for our live streaming, please register today.


I should preface this short discussion by saying that I'm scarcely cut out to be raising a venture capital fund to target investments in SENS rejuvenation research companies and other useful ventures likely to help produce effective treatments for aging - ways to extend healthy life and defeat age-related disease. To assemble a venture fund requires superb connections to start with, and then successfully running said fund after you've persuaded people to put tens of millions into your care requires a whole set of other skills and experience that I lack, and in truth have no great interest in acquiring. You might look at the venture capital aptitude test for an only slightly exaggerated way to assess your own suitability for this line of work.

There are venture capitalists out there today raising funds for longevity-related investments in biotechnology and medical development, however. This is a natural consequence of deep pockets like Google and Abbvie becoming involved in the field, as well as the large sums of money being invested in ventures like Human Longevity Inc. Ironically, Human Longevity is actually a well-dressed personalized medicine company, with little to do with the enhanced longevity the principals talk about, but appearance counts for a lot in the calculations being made behind the scenes. Where there are deep pockets, there are potential acquirers for new companies, and so the nascent field of treating aging has become much more attractive as a place to start new companies. Combine that with growing awareness of the state of the science, very much on the verge and ready to deliver new technologies at a steady pace in the years ahead, and it explains the interest new seen in portions of the venture capital community.

If I were going to raise a fund to profit from the first decade of the SENS rejuvenation biotechnology industry, small but soon to grow, it would be under terms that earmarked 10% or so of capital for funding research. Let us say - to simplify greatly - that venture funds have a lifetime of seven to ten years before they dissolve and return gains or losses to the investors. A successful biotechnology company focused on a single class of therapies, starting out with a working technology fresh from the labs, may run five years from start to acquisition, or to going public, though that second option has lost its popularity these days. Either of those endpoints would close out the participation of a fund invested in that company: the fund owners would count their profits at that point. These timelines allow a venture fund with capital earmarked for research to selectively make non-profit donations to fund research groups in the first couple of years of its existence. The idea in doing so is to establish strong relationships with those groups working on technologies that are plausibly quite close to the point at which a demonstration can be made, a drug candidate established, or other suitable point to launch a startup is reached, and then push that research across the finish line. At that point, the fund then invests in the resulting startup.

Venture funds make all of their profits from the very few outstanding successes they invest in. They lose money on more than half of their investments, and manage only a small profit on most of the rest. This is why venture capitalists behave in the way they do: they need to nurture companies that swing for the fences so as to become enormous successes if they do succeed. If you have a great idea for a sustainable business that cannot achieve this goal, and flattens out at merely large and successful, then that business is not the right fit for venture funding. Given this distribution of gains from venture investment, I suspect that a fund could earmark considerably more than 10% of its capital for research and still do very well by the method I outline above. You still have to sell this earmark to the people who will be investing in your fund, however, and they will probably require some convincing as the number grows.

I should emphasize that good venture capitalists provide a lot of aid to their portfolio companies. They are far from being just a source of money. The idea of using a portion of the fund to advance the necessary state of the science so as to create startups to invest in, and becoming very familiar with the research community as this takes place, is really just an acknowledgement that the process of development and creation of wealth doesn't start at the point at which a company is incorporated. That is quite some way down the line from the true starting point. If venture funds can aid and nurture growth companies, they can also reach further back down the development pipeline to aid and nurture research groups.

One of the reasons that this strategy isn't seen in the wild is, I suspect, that it is in fact very hard to gather the right connections and knowledge to pick winners in the laboratory. The present situation for SENS rejuvenation research may be quite uncommon, in that there are (a) numerous lines of work that are not heavily funded, but that should yield a large number of good approaches to therapies if completed, and (b) knowledge and connections in the SENS Research Foundation and the surrounding community sufficient to identify these opportunities. Further, the approach of creating startups by funding research probably doesn't scale very well from the point of view of a fund organization, in that the fund would have to make a comparatively large number of investments in research and seed level rounds in order to generate the opportunity for a smaller number of larger and later round investments. For a fund of tens of millions in capital, this is not a problem, but this is not a strategy that much larger funds could adopt given the way they are currently staffed and organized. There are only so many hours in the day, and there are only so many opportunities for smaller investments; you can't fit a whale into a fish tank.

Still, this is, I think, something well worth considering as our community moves forward and venture capitalists join our ranks. We have this opportunity, possibly uncommon, to reach back past the point at which companies start, to build hybrids of venture funds and research institutes focused on the most promising biotechnologies of rejuvenation and longevity. It would be a shame to let it go to waste.



Many signs of age-related disease start as early as the 30s, damage that is asymptomatic and minimal, but nonetheless exactly the same type of dysfunction that will later, when present to a much greater degree, cause age-related disease, frailty, and death. This is true of measures of cognitive decline for example, and here researchers demonstrate that the physical signs of Alzheimer's disease in the brain can start to occur comparatively early in life as well. It is a reminder that rejuvenation treatments based on damage repair, once developed, are not only for the old, but that everyone much over the age of 30 should use them for prevention.

Alzheimer disease has an asymptomatic stage during which people are cognitively intact despite having substantial pathologic changes in the brain. While this asymptomatic stage is common in older people, how early in life it may develop has been unknown. To test the hypothesis that asymptomatic Alzheimer disease lesions may appear before 50 years of age, we microscopically examined the postmortem brains of 154 people aged 30 to 39 years (n=59) and 40 to 50 years (n=95) for specific Alzheimer lesions: beta-amyloid plaques, neurofibrillary tangles, and tau-positive neurites. We genotyped DNA samples for the apolipoprotein E gene (APOE).

We found beta-amyloid lesions in 13 brains, all of them from people aged 40 to 49 with no history of dementia. These plaques were of the diffuse type only and appeared throughout the neocortex. Among these 13 brains, five had very subtle tau lesions in the entorhinal cortex and/or hippocampus. All individuals with beta-amyloid deposits carried one or two APOE4 alleles. Among the individuals aged 40 to 50 with genotype APOE3/4, 10 (36%) had beta-amyloid deposits but 18 (64%) had none. Our study demonstrates that beta-amyloid deposits in the cerebral cortex appear as early as 40 years of age in APOE4 carriers, suggesting that these lesions may constitute a very early stage of Alzheimer disease. Future preventive and therapeutic measures for this disease may have to be stratified by risk factors like APOE genotype and may need to target people in their 40s or even earlier.


Researchers have found that a reduced level of insulin-like growth factor 1 (IGF-1) in mice accelerates the progression of atherosclerosis, one of the more dangerous of age-related cardiovascular issues. Atherosclerosis involves the buildup of fatty deposits inside blood vessels, resulting from a cycle of damage and inflammation that starts with oxidized lipids, draws in macrophage cells that become overwhelmed and die, and creates growing plaques made up of of fats and cellular debris. The plaques narrow important blood vessels, contributing to hypertension and detrimental cardiovascular remodeling. When plaques rupture in their later stages, the result is blockage of important blood vessels that causes a stroke.

The researchers here suggest that increasing circulating IGF-1 above normal levels may slow the progression of atherosclerosis, though have yet to put together a demonstration of this, and it it isn't always the case that changes in the amount of a specific protein are mirrored in both directions. In this study, harmful effects due to lower levels of IGF-1 appear to result from reduced function of the macrophage cells responsible for clearing up damage in blood vessel walls. Other research groups have in recent years proposed enhancing macrophage capabilities to better cope with the mechanisms of atherosclerosis, but ultimately the best approach is to build some form of targeted therapy that can clear all of the damage and debris, not just somewhat improve existing systems so as to slow down its progression.

Atherosclerosis is a condition in which plaque builds up inside the arteries, which can lead to serious problems, including heart attacks, strokes or even death. Now, researchers have found that Insulin-like Growth Factor-1 (IGF-1), a protein that is naturally found in high levels among adolescents, can help prevent arteries from clogging. They say that increasing atherosclerosis patients' levels of the protein could reduce the amount of plaque buildup in their arteries, lowering their risk of heart disease. "The body already works to remove plaque from arteries through certain types of white blood cells called macrophages. However, as we age, macrophages are not able to remove plaque from the arteries as easily. Our findings suggest that increasing IGF-1 in macrophages could be the basis for new approaches to reduce clogged arteries and promote plaque stability in aging populations."

Researchers examined the arteries of mice fed a high-fat diet for eight weeks. IGF-1 was administered to one group of mice. Researchers found that the arteries of mice with higher levels of IGF-1 had significantly less plaque than mice that did not receive the protein. Since the macrophage is a key player in the development of atherosclerosis, the researchers decided to investigate potential anti-atherosclerosis effects of IGF-1 in macrophages. "We examined mice whose macrophages were unresponsive to IGF-1 and found that their arteries have more plaque buildup than normal mice. These results are consistent with the growing body of evidence that IGF-1 helps prevent plaque formation in the arteries." The researchers also found that the lack of IGF-1 action in macrophages changed the composition of the plaque, weakening its strength and making it more likely to rupture and cause a heart attack. The researchers plan to conduct the same study on larger animals before eventually studying human subjects.


Of late, there has been a growing interest in exploring mechanisms related to nicotinamide adenine dinucleotide (NAD) and the way in which their operation changes over the course of aging. This research has grown out of the last decade of attempts to produce calorie restriction mimetic drugs that might modestly slow aging, lengthy efforts that have resulted in a better understanding of some aspects of metabolism, but few leads to drug candidates. NAD is important in mitochondrial function, and many methods of slowing aging in laboratory species - calorie restriction included - involve changes in this part of cellular biochemistry. Increased levels of NAD in mice appear to produce better mitochondrial function and greater cellular housekeeping efforts, the second of which is fairly common among interventions that influence mitochondrial biochemistry. The flux of reactive oxygen species produced by mitochondria in the course of generating energy store molecules for the cell is used as one of many intracellular signals, and produces the housekeeping reaction when it grows larger.

Researchers have identified the enzyme, called CD38, that is responsible for the decrease in nicotinamide adenine dinucleotide (NAD) during aging, a process that is associated with age-related metabolic decline. Results demonstrated an increase in the presence of CD38 with aging in both mice and humans. "Previous studies have shown that levels of NAD decline during the aging process in several organisms. This decrease in NAD appears to be, at least in part, responsible for age-related metabolic decline." Researchers have shown that CD38, an enzyme that is present in inflammatory cells, is directly involved in the process that mediates the age-related NAD decline. Comparing 3- to 32-month-old mice, researchers found that levels of CD38 increased at least two to three times during chronological aging in all tissues tested, including the liver, fat, spleen and skeletal muscle.

To determine if the increase in CD38 observed in mice was also present in humans, researchers compared the levels in groups of individuals who were approximately 34-years-old to groups of individuals who were approximately 61-years-old. Similar to their observations in mice, researchers found that CD38 increased up to two-and-a-half times in the fat tissue of older individuals. "The future of our research will be to develop compounds that can inhibit the function of CD38 to increase NAD levels during aging. We are also investigating the mechanisms that lead to the increase in CD38 during the aging process."


Besides living for nine times longer than other, similarly sized rodent species, naked mole rats are also highly resistant to cancer, to the point at which only a handful of cases have ever been observed. The scientific community is seeking the roots of this cancer resistance to see if the mechanisms involved can form the basis for human therapies. So far, research has centered on differences in the biochemistry of tumor suppressor gene p16, and hyaluronan, which may be responsible for activating p16 more aggressively in naked mole rats. Here, researchers identify another possibly relevant difference in mechanisms relating to the tumor suppressor gene ARF; in naked mole-rats, unlike other mammals, disabling this gene causes cells to halt replication and become senescent. This may act to close off a variety of mutational paths to cancer, changes that will spawn tumors in mice, but not in naked mole rats.

The research team took skin fibroblast tissue from adult naked mole-rats and reprogrammed the cells to revert to pluripotent stem cells. These are called induced pluripotent stem cells (iPSCs) and, like embryonic stem cells, are capable of becoming any type of tissue in the body. However, these stem cells can also form tumours called teratomas when transplanted back into the animals. When the naked mole-rats' iPSCs were inserted into the testes of mice with extremely weak immune systems, the team discovered that they didn't form tumours in contrast to human iPSCs and mouse iPSCs. Upon further investigation, they found that a tumour-suppressor gene called alternative reading frame (ARF), which is normally suppressed in mouse and human iPSCs, remained active in the mole-rat iPSCs.

The team also found that ERAS, a tumorigenic gene expressed in mouse embryonic stem cells and iPSCs, was mutated and dysfunctional in the naked mole-rat iPSCs. When the researchers disabled the ARF gene, forced the expression of the mouse ERAS gene in the naked mole-rat iPSCs, and then inserted them into the mice, the mice grew large tumours. When researchers suppressed the ARF gene in naked mole-rat cells during the reprogramming process to iPSCs, the cells stopped proliferation with sign of cellular senescence, while the opposite happens with mouse cells. Researchers theorize that this further helps protect the naked mole-rat by reducing the chance for tumour formation. They call this ARF suppression-induced senescence (ASIS) and it appears to be unique to the naked mole-rat.


Researchers here link vascular calcification in aging with an accumulation of one of a number of related forms of undesirable metabolic waste. One of the root causes of degenerative aging is this accumulation of hardy forms of metabolic waste that our biochemistry either finds hard to break down, or simply cannot break down. This waste accumulates in cell lysosomes as a mix of compounds usually called lipofuscin or drusen, depending on the context. Lysosomes are the recycling plants of the cell, and this accumulation causes them to become dysfunctional, leading ultimately to some form of garbage catastrophe as cellular maintenance breaks down. The SENS Research Foundation is one of the few groups funding work to find ways to safely remove lipofuscin compounds, largely based on mining the bacterial world for enzymes that can be used as the basis for small molecule drugs. Once developed, clearing lipofuscin will be a form of rejuvenation therapy, removing one of the contributing causes of a number of age-related conditions.

One of the constituent compounds of liposfuscin is 7-ketocholesterol, which is known to contribute to macular degeneration as well as to various forms of damage to blood vessel walls, such as those that can lead to atherosclerosis. The SENS Research Foundation has had some success in finding candidates to digest 7-ketocholesterol, but this is still a work in progress. The research noted here provides yet another argument for the research community to invest more time and funding into finding ways to effectively break down these harmful lipofuscin constituents: vascular calcification contributes to the development of a range of ultimately fatal cardiovascular conditions.

Vascular calcification, characterized by the deposition of hydroxyapatite in cardiovascular tissue, is commonly observed in patients with diabetes mellitus, chronic kidney disease (CKD) and atherosclerosis. Several studies have indicated that the presence of calcification in coronary arteries correlates with an increased risk of myocardial infarction and is an independent predictor of future cardiovascular events in asymptomatic patients. Accordingly, treatment of vascular calcification is directly linked to decreased cardiovascular mortality. Recent findings suggest that the development of calcification is an active cell-regulated process similar to osteogenesis. Two pathological processes, osteoblastic differentiation and apoptosis of vascular smooth muscle cells (VSMCs), are mainly involved in the development of vascular calcification.

Recent studies have showed that oxidized low-density lipoprotein (oxLDL), enriched in atherosclerotic plaques, promotes osteoblastic differentiation and calcification of VSMCs. Oxysterols, such as 7-ketocholesterol (7-KC), are major components of oxLDL and are associated with its cytotoxicity. We have previously reported that 7-KC promotes osteoblastic differentiation and apoptosis of VSMCs, resulting in progression of calcification. However, whether the effects of 7-KC on calcification are related to autophagy is still unknown. Our aim was therefore to unravel the relationship between ALP and the progression of calcification by 7-KC.

The formation and accumulation of 7-KC often occur in lysosomes, and 7-KC promotes accumulation of unesterified cholesterol in the lysosome. Accumulation of cholesterol causes impairment of the lysosomal membrane, resulting in inhibition of the lysosome fusing with the autophagosome or endosome. Because 7-KC is also known to induce permeabilization of the lysosomal membrane, impairment of autophagy process by 7-KC may due to alteration of the lysosomal membrane potential. Subsequent to autophagy disruption, 7-KC causes the failure of lysosomal enzyme activity along with enlargement of lysosomes.

In our model, a high concentration of 7-KC caused further increase in calcification, and this exacerbation of calcification was closely related to apoptosis. In contrast, a low concentration of 7-KC accelerated calcification without apoptosis, and this acceleration of calcification was alleviated by inhibition of lysosomal-dysfunction-dependent oxidative stress. Recent studies have indicated that 7-KC induces the loss of mitochondrial transmembrane potential which is a marker of mitochondrial injury. Moreover, the decline of lysosomal function causes the defect of mitochondrial turnover, which induces the acceleration of reactive oxygen species (ROS) generation. These lysosomal-mitochondrial axes also induce the interaction between ROS generated from mitochondria and iron derived from lysosome, leading to the intralysosomal accumulation of more reactive ROS. In conclusion, we showed for the first time that 7-KC induces oxidative stress via lysosomal dysfunction, resulting in exacerbation of calcification.


If the research community is to win in the fight to cure cancer, and win soon enough to matter for all of us, then the focus must be on technology platforms that can be easily and cheaply adapted to many different types of cancer. The biggest strategic problem in the field is that most of the expensive, time-consuming efforts to develop new therapies are only applicable to one or a few of the hundreds of types of cancer. Immunotherapies based on the use of chimeric antigen receptors are an incremental step towards solving this problem, an improvement on the present situation because this technology may cut the cost of tailoring an immunotherapy to each specific type of cancer. This approach has worked very well in trials targeting leukemia, but there was some question as to how to adapt it for use in solid tumors, and whether it would work in this context. Fortunately, it seems that this next step forward has now been accomplished, at least in a preliminary animal study:

Chimeric antigen receptor (CAR) T cell therapy, which edits a cancer patient's T cells to recognize their tumors, has successfully helped patients with aggressive blood cancers but has yet to show the ability to treat solid tumors. To overcome this hurdle, researchers genetically engineered human T cells to produce a CAR protein that recognizes a glycopeptide found on various cancer cells but not normal cells, and then demonstrated its effectiveness in mice with leukemia and pancreatic cancer. "This is the first approach using a patient's own immune cells that can specifically target this class of cancer-specific glycoantigens, and this has the great advantage of applicability to a broad range of cancers. Future cancer immunotherapies combining the targeting of cancer-specific carbohydrates and cancer proteins may lead to the development of incredibly effective and safe new therapies for patients."

T cells are collected from the patient's blood and genetically engineered to express cell-surface proteins called CARs, which recognize specific molecules found on the surface of cancer cells. The modified T cells are then infused into the patient's bloodstream, where they target and kill cancer cells. In recent clinical trials, CAR T cell therapy has dramatically improved the outcomes of blood cancer patients with advanced, otherwise untreatable forms of leukemia and lymphoma. But the full potential of CARs for treating solid tumors has not been reached because they have targeted molecules found on the surface of both normal cells and cancer cells, resulting in serious side effects.

The cancer cell marker the team identified was a specific change in protein glycosylation, that is, a unique pattern of sugars decorating a protein found on the cell surface. The researchers developed novel CAR T cells that express a monoclonal antibody called 5E5, which specifically recognizes a sugar modification - the Tn glycan on the mucin 1 (MUC1) protein - that is absent on normal cells but abundant specifically on cancer cells. The 5E5 antibody recognized multiple types of cancer cells, including leukemia, ovarian, breast, and pancreatic cancer cells, but not normal tissues. "This is really the first description of a CAR that can target multiple different solid or liquid tumors, without apparent toxicity to normal cells. While it may not be a universal CAR, it is currently the closest thing we have." Moreover, injection of 5E5 CAR T cells into mice with leukemia or pancreatic cancer reduced tumor growth and increased survival. All six mice with pancreatic cancer were still alive at the end of the experiment, 113 days after treatment with 5E5 CAR T cells. Meanwhile, only one-third of those treated with CAR T cells that did not target Tn-MUC1 survived until the end of the experiment.


Sarcopenia is the name given to progressive age-related loss of muscle mass and strength. Here one possible contributing cause of the condition is explored: reduced levels of a protein involved in the quality control of mitochondria, which may allow damaged mitochondria to accumulate more readily in muscle tissue. Researchers have been lobbying for a decade to have sarcopenia formally defined as a medical condition, but that hasn't yet come to pass. The causes of sarcopenia are still debated; there are many possible contributions with plausible supporting evidence, but it isn't at all clear as to how they interact or which are the most important. Researchers have suggested fat tissue infiltration into muscles, the lack of exercise prevalent in older populations, rising levels of inflammation, failing leucine metabolism, vascular aging in muscles, Wnt signaling changes, and declining activity in muscle stem cells, among others. Interventions that slow aging, such as calorie restriction, also tend to slow the progression of sarcopenia, but beyond that and exercise there isn't yet much that can be done about this condition.

At about 55 years old, people begin to lose muscle mass, this loss continues into old age, at which point it becomes critical. The underlying causes of sarcopenia are unknown and thus no treatment is available for this condition. A study has discovered that Mitofusin 2 is required to preserve healthy muscles in mice. These researchers indicate that this protein could serve as a therapeutic target to ameliorate sarcopenia in the elderly, observing that during aging mice specifically lose the expression of Mitofusin 2 in muscle. They demonstrate that low activity of this protein in 24-month old mice (the equivalent of a person aged 80) is directly associated with muscle wastage and the sarcopenia observed. The scientists confirm the link between the loss of Mitofusin 2 and muscle aging when the expression of the protein is suppressed in the muscles of 6-month-old animals (equivalent to a person of 30) as these animals showed accelerated aging, reproducing the muscle conditions of aged mice.

"Over five years we have collected sufficiently significant evidence that demonstrates the contribution of Mitofusin 2 to the maintenance of good muscle health in mice and that allows us to consider a therapeutic strategy for sarcopenia. Sarcopenia is not a minor issue because it impedes some elderly people from going about their everyday lives. If we want to boost the health of the elderly then this problem has to be addressed." The researchers are running a study in collaboration with physicians working in geriatric medicine to demonstrate that Mitofusin 2 is also repressed in human aging. In addition, this group also has the technology ready to search for pharmacological agents capable of boosting Mitofusin 2 activity.

Mitofusin 2 is a mitochondrial protein involved in ensuring the correct function of mitochondria, and it has several activities related to autophagy, a crucial process for the removal of damaged mitochondria. The loss of Mitofusin 2 impedes the correct function of mitochondrial recycling and consequently damaged mitochondria accumulate in muscle cells. The researchers have also identified and described an autophagy rescue system which kicks in regardless of Mitofusin 2 levels and allows cells to partially recover the mitochondrial recycling system in skeletal muscle. The scientists suggest that this could serve as an alternative metabolic mechanism used by Mitofusin to increase skeletal muscle autophagy and to maintain a healthier mitochondrial system.


Diabetes of any variety is a damaging distortion of normal metabolism. Once in progress, it causes further harm on an ongoing basis. The type 2 diabetes most often seen in older people is a lifestyle condition: the vast majority of cases are caused by being overweight, and can be reversed even at a late stage by adoption of a low-calorie diet and consequent weight loss. So when researchers note that being diabetic greatly increases heart attack risk, it is an interesting question as to the degree to which this is because patients are overweight, independently of diabetes, versus the degree to which it is due to the mechanisms of diabetes itself. Excess visceral fat tissue produces chronic inflammation, and inflammation speeds the development of all of the common age-related conditions, but here the data suggests that weight should also be given to processes and damage specific to diabetes itself.

Having diabetes increases the risk of dying from the effects of a heart attack by around 50 per cent, a study has found. Researchers tracked 700,000 people who had been admitted to hospital with a heart attack between January 2003 and June 2013. Of these, 121,000 had diabetes. After stripping out the effects of age, sex, any other illnesses and differences in the emergency medical treatment received, the team found stark differences in survival rates. People with diabetes were 56 per cent more likely to have died if they had experienced a ST elevation myocardial infarction (STEMI) heart attack - in which the coronary artery is completely blocked - than those without the condition. They were 39 per cent more likely to have died if they had a non-ST elevation myocardial infarction (NSTEMI) heart attack - in which the artery is partially blocked - than those without diabetes.

"We knew that following a heart attack, you are less likely to survive if you also have diabetes. However, we did not know if this observation was due to having diabetes or having other conditions which are commonly seen in people with diabetes. This paper is the first to conclusively show that the adverse effect on survival is linked to having diabetes, rather than other conditions people with diabetes may suffer from. These results provide robust evidence that diabetes is a significant long-term population burden among patients who have had a heart attack. Although these days people are more likely than ever to survive a heart attack, we need to place greater focus on the long-term effects of diabetes in heart attack survivors."


Cognitive decline with aging is a patchwork of scores of progressive failures in different systems in the brain, all proceeding at their own pace. The research noted here is a good example of the way in which researchers try to pick apart the whole into comprehensible pieces, a necessary part of the much lengthier process of mapping specific declines to specific damage and change in the brain:

Staying on topic may be more difficult for older adults than it is for younger people because older adults begin to experience a decline in what is known as inhibition - the ability to inhibit other thoughts in order to pursue the storyline. Evidence for inhibition deficits in older adults has appeared in studies that task participants with completing a familiar phrase with an unfamiliar word. For example, when asked to complete out loud the sentence "I take my coffee milk and ..." with the word "pajamas" instead of "sugar," older adults are more likely to first respond with "sugar" than young participants because they have a harder time inhibiting the high-probability word to complete the sentence. Decline in inhibition also can affect visual perception, as is demonstrated by new research. Inhibition is an important part of neural processing throughout the brain, and it plays a significant role in visual perception. For example, evidence suggests that when we look at an object or a scene, our brain unconsciously considers alternative possibilities. These competing alternatives inhibit one another, with the brain effectively weeding out the competition before perceiving what is there. With regard to vision, age-related declines in the efficiency of inhibitory processes have been demonstrated in research involving simple perception tasks, such as the ability to detect symmetry and discriminate between shapes.

In this study, the researchers were interested specifically in what is known as figure-ground perception, in which two areas in a person's visual field share a border. If you imagine a white heart on a black background, for example, the heart is the "figure" - with its definitive shape - and the black background is the "ground," which seems to simply continue behind the figure. In the lab, researchers showed on a screen a series of small, symmetrical white-on-black silhouettes to two different groups: young participants with an average age of about 20 and older participants with an average age of about 66. Participants were asked to determine whether each white "figure" depicted a familiar object, such as an apple, or a novel object - a meaningless shape.

"For a long time my students and I have been investigating how we see the world. Our work has suggested that the brain first detects all the borders in a scene and then for every border, accesses object properties - essentially different interpretations - on both sides. These two interpretations compete by inhibiting each other, and whichever one has more evidence in favor of it is going to exert more inhibition on the other one to win the competition." In the end, younger and older participants both came to the same conclusions about whether the white objects were familiar. However, it took longer overall for older adults to come to that conclusion, especially when images presented more inhibitory competition. The findings support and further evidence that older adults experience age-related deficits in inhibition related to vision.


Researchers are attempting to understand the biochemistry of limb and organ regeneration, exceptional cancer resistance, and hibernation in a number of species in order to see whether they can form the basis for therapies or enhancements in humans. Here, hibernation is the focus:

Novel adaptations discovered in hibernating animals may reveal ways to mitigate injuries associated with strokes, heart attacks and organ transplants. A person typically takes a long time to recover from cardiac surgery or organ transplant. This is in part because organ tissue is damaged when blood flow ceases or is reduced when a heart stops or an organ is removed. Tissue is also damaged when blood flow is restored and the body's metabolic machinery is not able to safely handle the returning rush of oxygenated blood. Protection of tissues following cardiac arrest or organ transplant has remained an elusive scientific target, despite significant research and promising data.

In 2009, researchers began collaborating to identify how a hibernating Arctic ground squirrel's heart can survive what is akin to repeated cardiac arrests. Unlike other animals, Arctic ground squirrels can lower their metabolism to 2 percent of their normal rate, which allows them to essentially shut down bodily functions they don't need and, importantly, puts their organs in a state of suspended animation. The researchers collected and analyzed proteins associated with heart muscle from cooled, hibernating Arctic ground squirrels in which blood flow had been stopped. They repeated the analyses on heart proteins from active summer Arctic ground squirrels and rats, which don't hibernate.

By comparing the various proteins produced and the metabolic changes within each animal, they identified novel internal adaptive mechanisms by which ground squirrels cope with cold and other stressors and how those mechanisms relate to blood flow problems associated with cardiac surgery. One such mechanism is the ability of hibernators to exclusively use lipids, which include fats, vitamins and hormones, as metabolic fuel instead of burning carbohydrates, as humans do during surgeries. Understanding this unique model of extreme metabolic flexibility may help scientists develop strategies that enable doctors to "switch" the metabolism of a patient who has suffered a stroke, cardiac injury or hypothermia to resemble that of a hibernator and thereby improve survival and recovery. The authors anticipate that the knowledge gained from this study could be applied to organ protection in nonhibernators and ultimately in patients undergoing heart surgery and transplantation, and for victims of cardiac arrest, trauma and hypothermia.


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