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Fight Aging! Newsletter, July 20th 2015

FIGHT AGING! NEWSLETTER
July 20th 2015

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.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENTS

  • 2015 Fundraising: 70,000 Pledged to the Matching Fund So Far
  • Aging as the Greatest Disease of All
  • Rejuvenation Biotechnology Update for Q3 2015
  • As Expected, Nothing of Value Emerged at the White House Conference on Aging
  • Persuasion as Activism for Rejuvenation Research
  • Latest Headlines from Fight Aging!
    • A Review of the Use of C. Elegans in Aging Research
    • p53 and Rapamycin Have Additive Effects on mTORC1
    • A Recent Interview with Aubrey de Grey of the SENS Research Foundation
    • A Novel Contribution to Age-Related Hearing Loss
    • There are Always Those Who Try to Tell Us that Greater Longevity Will Be a Disaster
    • Ultrasound Can Accelerate Skin Healing in the Elderly
    • Grassroots Political Advocacy for Longevity in Europe
    • A Merging of Advocacy for Technological Convergence and Faster Medical Research
    • More on Aging Research at the Buck Institute
    • Resveratrol as a Cautionary Tale

2015 FUNDRAISING: 70,000 PLEDGED TO THE MATCHING FUND SO FAR
https://www.fightaging.org/archives/2015/07/2015-fundraising-70000-pledged-to-the-matching-fund-so-far.php

Beginning on October 1st and lasting though to the end of the year we'll be running our latest grassroots fundraiser to support the work of the SENS Research Foundation. This remains perhaps the only charitable organization in the world devoted to removing all the hurdles standing in the way of progress in rejuvenation research: halting and reversing all age-related disease by repairing the known common root causes. Most of this work involves funding and cultivating research programs in vital areas overlooked by the scientific mainstream, wherein a modest investment in capital, networking, and persuasion over a few years can get things moving. There is a well-oiled, massive infrastructure already in place that picks up and develops medical research that reaches a certain point of maturity and demonstrable results, and the principal challenge for potential rejuvenation therapies at the present time largely lies in reaching that point.

Help Us to Build a Matching Fund: 70,000 and Counting

This year, just as in 2014, we are preparing for the October fundraiser by building a matching fund. I kicked things off with a 25,000 contribution from Fight Aging! and called for people to match as much as they can. So far, Josh Triplett, Christophe and Dominique Cornuejols, and forever-healthy.org have stepped up to swell the fund to 70,000. Can you help us make this a bigger round number? All pledges are tax-deductible and go to fund SENS Research Foundation programs.

We Raise Funds to Start the Avalanche

We raise funds for rejuvenation research because our contributions make a difference, because no-one other than philanthropists funds very early-stage medical research, and because as little as a few tens of thousands or hundreds of thousands of dollars is enough to start the avalanche. You probably think of medicine as one of the most expensive undertakings in the world today. That's certainly true of bringing therapies from the lab into the clinic, when a single clinical trial can cost tens of millions, but the business of actually making the initial prototypes in the lab? The cost of that work is startlingly low in this age of biotechnology: a grad student with 10,000 to spend can do more today in a semester than an entire laboratory staff with a budget of millions could have achieved twenty years ago. Building the prototypes of tomorrow's therapies is something that is well within our means when we collaborate.

A Proven Method: In 2008 Philanthropic Funding for SENS Started an Avalanche

So this is a golden age for medicine, in which people of modest means, you and I, can fund the first proof of concept for a rejuvenation treatment based on repair of cellular and molecular damage. The SENS research programs themselves have been underway for long enough that we can already see the signs of success, modest funding and collaboration carried out years ago blossoming into an active development program with a large budget. Started in 2008, the SENS programs at the Methuselah Foundation and then at the SENS Research Foundation funded collaborative early stage work on mitochondrial repair technologies with the lab of Marison Corral-Debrinksi in Paris, moving that work into animal models and demonstrating success in repairing specific mitochondrial DNA mutations associated with the hereditary blindness condition LHON. This was far enough for other funding sources and collaborators to join in and reinforce this success.

By 2013 Gensight was founded to commercialize this technology, and today that company devotes tens of millions to finalizing and bringing to the clinic a SENS vision for mitochondrial repair technologies, with an initially limited application to cure inherited mitochondrial disease. Every advance in the state of the art hammered out by this well-funded effort can later be adapted for therapies capable of repairing the forms of mitochondrial mutation that contribute to degenerative aging. Gensight is building one of the robust technology platforms needed for near future rejuvenation treatments.

Those of us who made charitable contributions to the very limited SENS budget as it was all the way back in 2008 had a hand in setting this avalanche in motion. This is how the model works: support early research and the scientists performing that work sufficiently well, by donating to an organization that has great experience in doing just that, and a few years later the funding flowing into ongoing development will expand far beyond your contribution.

By Helping Now, You Start the Avalanches Leading into the Early 2020s

This is a long game we're playing here. By helping the Fight Aging! fundraiser for the SENS Research Foundation this year, you support and expand research programs that will lead to the Gensights of the 2020s, companies yet to exist whose backers will pour tens of millions into creating medical technologies needed for human rejuvenation therapies. Join us in helping to create the next stage in this journey towards a better world, one in which aging and all of its pains and frailties and medical conditions are banished to the history books.

Spread the Word!

Point a friend to the Fight Aging! FAQ. Tell someone you know about the SENS Research Foundation and what it is they do. Pass around one of this year's fundraising posters, or dare I ask, improve upon them. The grand tapestry of success is built of small choices to help, and all of us can choose to make a difference.

AGING AS THE GREATEST DISEASE OF ALL
https://www.fightaging.org/archives/2015/07/aging-as-the-greatest-disease-of-all.php

Here I'll point you to a discussion paper published last month on the topic of whether or not aging is a disease: it is on the whole eminently sensible and well worth reading, and it is a pity that the vast majority of the people who would most benefit from looking over this paper will never even notice that it exists.

In recent years a large amount of ink has been spilled in the debate over whether or not aging should be either colloquially or formally defined as a disease, although this is a discussion almost entirely restricted to the scientific community, invisible to the world at large. As I've noted in the past this really wouldn't matter all that much, save for the fact that medical development and provision of medicine is heavily regulated. In countries like the US it is literally the case that everything to do with medicine that is not explicitly permitted and on a list somewhere at the FDA is by default forbidden and illegal. Treating aging is at present not on that list - and even some conditions of aging such as sarcopenia are not yet on the list, despite years of lobbying. The wheels move exceedingly slowly.

Thus underlying any debate over what exactly we mean by disease and what exactly we mean by aging is the fact that funding and the pace of progress in aging research rests on which boxes are checked by various bureaucrats. Powerful incentives steer those who work within the regulatory straitjacket, and changing the use of language to better move with the imposed limits is almost the least of harmful outcomes. Still, there are other reasons to argue for aging to be called a disease, such as clarifying the position of the research community for the layperson, and aiming for greater support for the goal of bringing aging under medical control.

The aging-disease false dichotomy: understanding senescence as pathology

Is our understanding of aging still in the dark ages? Over the course of the last centuries a gradual process of enlightenment has taken place in many different areas of human understanding, in which traditional views have been overturned by new knowledge borne of reason and the results of scientific investigation. A more realistic view of things, though it can initially cause controversy by upsetting traditional views and practices, ultimately enables more effective and more ethical action. Such a process of rationalization has profoundly affected the field of medicine, and the way we view many health-related issues. Yet when it comes to aging this salutary process of rationalization is still in its early stages. Here a salient example is the widespread and, arguably, false view that aging is distinct from disease and therefore not appropriate for medical attention - and even something benign and wholesome.

I have encountered many erroneous views during my 20 years working as a biogerontologist, often from members of the public but also from clinicians, gerontologists, and academics of various other specialities. A particular source of error is the false dichotomy drawn between aging and disease. When biogerontologists speak of aging they usually mean senescence. Is senescence a disease? The very word senescence, denoting deterioration leading to death, certainly carries that implication. If senescence is an evolutionary adaptation, this would to some extent support the idea that aging is non-pathological. But this reasoning would also involve a fallacious appeal to nature, a false equation of human evolutionary fitness with well being. If human aging did in fact evolve to benefit the species by ridding it of worn out elderly people, this should not deter us from looking for treatments for Alzheimer's disease and cancer.

Is aging distinguishable from pathology? Given the similarity in meaning between disease and pathology, asking this is similar to asking whether aging is a disease. It has been concluded that there is no clear distinction between aging and pathology, and this is supported by accumulating evidence from biology. Treatments that extend lifespan in animal models typically delay age-related pathology and extend youth span: life extension only occurs as the result of prevention of pathology, whether the pathology is caused by aging or by something else. Life extending treatments in the laboratory invariably decelerate aging (rather than stopping or reversing it); this results in a delay in the appearance of age-related pathology (extending youthspan), but then such pathologies still eventually appear, causing illness, and death.

A goal of preventing diseases of aging without altering aging itself makes little sense if aging itself is pathological, though it certainly makes sense to prioritize action against the more lethal pathologies. In a similar vein, the likelihood of recapitulating Tithonus's dreadful fate is very remote; in fact, to my knowledge no biogerontologist has ever generated a worm or fruitfly Tithonus in which life in a state of advanced senescence is greatly extended. Finally, the goal of enabling people to die without pathology, or of pure aging, is untenable if non-pathological senescence does not exist. In fact, the idea of elderly people dying of aging without pathology is plainly nonsense; among the defining properties of pathology, causing death is surely a sine qua non. (Yet I recently discussed with a former director of a major medical research funding agency the idea that elderly people can die without pathology, and found that they agreed with it).

It seems likely that advances in biogerontology will contribute to geroprotective interventions which hold back the pathologies of human aging; such interventions may well increase lifespan. A recurrent feature of arguments against treating aging is an over-emphasis on increased lifespan as an outcome, and neglect of alleviation of illness. Thus, to say: "I would like a longer life" may be presented as egoism or folly, but not "I would like to remain free of cancer." Likewise, one would not hold against someone infected with, say, malaria their wish not to die from the disease - and one would certainly not accuse them of egotism for wishing to extend their life. The point here is that, in the end, senescence is in many ways just like other severe diseases: it causes illness and death, and treating it results in a longer life. Critics of treating aging are often guilty of double standards, and of undervaluing the well being - and life - of older people.

To act ethically a realistic grasp of relevant facts is critical. This is particularly important for aging, the main cause of chronic disease and death in the world today. Yet traditional ideas about aging include some major misconceptions, including the aging-disease false dichotomy. It is to be hoped that such ideas do not misguide those responsible for the healthcare interests of older people, including those responsible for setting medical research priorities. Neglect resulting from misunderstanding aging may cause harm by allowing preventable illness, both now and in the future - given that geroprotection is most efficacious in the form of prevention. To achieve the best outcomes in terms of the future health of older people, it is vital to adopt a frank and rational attitude to aging. We must draw aside the rosy veil of tradition and face aging for what it is, and in all its horror: the greatest disease of them all.

REJUVENATION BIOTECHNOLOGY UPDATE FOR Q3 2015
https://www.fightaging.org/archives/2015/07/rejuvenation-biotechnology-update-for-q3-2015.php

The Methuselah Foundation and SENS Research Foundation collaborate to put out a quarterly newsletter on recent scientific advances for members of the 300, people who pledge to donate 25,000 over 25 years to research and development aimed at extending healthy life spans. The earliest members of the 300 collectively gave the first significant funding to the Methuselah Foundation when it launched, providing the resources needed to start the Mprize for longevity science and later the SENS rejuvenation research programs.

SENS research outgrew its roots and spun off into its own non-profit foundation back in 2009, but the staffs of the Methuselah Foundation and SENS Research Foundation continue to collaborate on various ventures. We're all chasing the same goal, after all, meaning the development of therapies that can collectively halt degenerative aging by periodically repairing its root causes. This class of technology can in principle prevent and cure all age-related disease: it is just a matter of building tools that are good enough at the various necessary forms of cell and tissue repair.

This quarter's newsletter turned up in my inbox today alongside a reminder that the Rejuvenation Biotechnology 2015 conference to be held on August 19th in San Francisco is still accepting registrations. Just as last year, this will be a meeting in the middle between industry and academia, building the bridges needed for the near future development of first generation rejuvenation therapies. The times are changing, and this will be just one of a range of well-subscribed events taking place each year, attended by people with a serious focus on the treatment of aging.

Rejuvenation Biotechnology Update, July 2015 (PDF)

Young capillary vessels rejuvenate aged pancreatic islets

The authors showed that in older mice, and in humans, evidence of damage to the pancreatic islet blood vessels could be observed. They took pancreatic islets from old mice and transplanted them into the eyes of young mice whose own β-cells had been destroyed with a drug so that they could produce no insulin on their own (a common model of "type 1" or "juvenile" diabetes). Remarkably, when placed in the environment of the young mouse eye, the islets from the old mice proliferated, developed a healthy blood supply, and were able to completely restore control of blood glucose and function as normal β-cells would in the young, type 1 diabetic mice. As strange as it sounds, these β-cells were able to do this from inside the eye.

This study is very provocative. Similarly to parabiosis experiments, removing aged pancreatic islet cells from their original host and exposing them to the younger host's intact blood vessels was able to restore their normal function. This lends credence to the idea that, at least in the case of pancreatic β-cells and diabetes, the aged tissue environment and not the aged cells themselves is the important determinant of functionality. As the authors point out, this finding provides hope that finding ways of restoring the vasculature of the pancreatic islets to a healthier state could be key in treating age-related type 2 diabetes/glucose homeostasis problems.

Scanning Ultrasound Removes Amyloid-β and Restores Memory in an Alzheimer's Disease Mouse Model

The researchers in this study found a non-pharmaceutical and non-invasive way to stimulate clearance of amyloid-β (Aβ) in the brains of AD mice. Repeated treatments with scanning ultrasound after injecting "microbubbles" of air into the blood of AD mice were able to induce movement of Aβ into the lysosomes (the "cellular incinerator") of microglia (cells that perform cleanup, among other functions, in the brain) in the brains of these mice. Meaningfully, the AD mice who received the ultrasound treatments showed improvements on three different memory tests compared to the control group.

The approach used in this study is very interesting because it does not rely on pharmacological or surgical means, but was able (at least in AD mice) to induce clearance of Aβ from the brain and improvements in memory. The mechanism may lie in the ability of the microbubbles in the blood to vibrate against the lining of the small capillaries in the brain, causing a gentle and temporary disruption of the blood-brain barrier and possibly allowing antibodies or other blood components to access the brain.

There are a few caveats, one of which is how well AD mice accurately model human AD. Many of these mice are genetically altered to produce large amounts of Aβ, and consequently develop symptoms similar to human AD, such as memory decline. But in humans, the majority of cases are not caused by a single genetic mutation. Another caveat: there is always the possibility that brain ultrasound could induce some kind of side effect in humans not observed in the mice, such as microvascular strokes, hemorrhaging, or inflammation - or that it would simply be ineffective because the ultrasound could not penetrate deep enough into the brain tissue of a human as could be done in a mouse with a comparatively tiny cranium and thin skull.

α-Synuclein Inclusions in the Skin of Parkinson's Disease and Parkinsonism

Several degenerative brain diseases (Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy, and others) share the common feature of protein aggregates (clumps) in the brains of patients, made of a protein called α-synuclein. These diseases are sometimes collectively referred to as "synucleinopathies." Since there are two vaccines currently in human clinical trials that are aimed at clearing α-synuclein aggregates (which will hopefully lead to restoration of function), and α-synuclein aggregates are known to be associated with functional impairments in people who have not yet developed full-blown PD or related disease, it would be useful to have a non-invasive test to determine who might need such a treatment, especially if this can be determined before overt disease develops.

There is a hypothesis that while α-synuclein may ultimately aggregate in the brain in PD, it may originate from other sources in the body, such as the gut. The fact that α-synuclein was found in the skin of a majority of PD patients tested is interesting, and it may even provide some basis for speculation that α-synuclein could come from the skin, or from multiple sources, migrate to the brain, and cause Parkinson's Disease. Skin and neural tissue share a common embryonic origin (the ectodermal germ layer), so both cell types may share some genetic program that leads α-synuclein production and accumulation. But this is all just speculation right now, and as is often the case with diseases of aging, it can be very difficult to determine the relationship between various factors and observations.

AS EXPECTED, NOTHING OF VALUE EMERGED AT THE WHITE HOUSE CONFERENCE ON AGING
https://www.fightaging.org/archives/2015/07/as-expected-nothing-of-value-emerged-at-the-white-house-conference-on-aging.php

The White House Conference on Aging was held a few days ago, but you didn't need to pay any attention. The event related to matters that have absolutely no bearing on the future of aging research or the future of aging itself: it focused on entitlements and organization of the process of dying, and had nothing to do with treating aging or medical research in any meaningful sense. There is a way to go yet before the ripples of revolution in scientific circles make their way to be seen by the majority of politicians and bureaucrats.

Representative governments are in essence an expression of conservatism, in the sense of seeking stasis, pursuing the preservation of the present situation. This is more or less human nature; it is the way groups of people react. There is resistance to change, even obviously beneficial change, and a desire to decorate and sustain the present status quo, no matter how terrible that status quo, no matter how it came about, and no matter how long it has been around. The inner ape seeks assurance that present circumstances have a permanence to them, that tomorrow will be the same as today. The possibility of change equates to a threat in this instinctive view of the world. We should be better than that, but put any hundred of us in a room together and we are not. The crowd is even more the ape than the individual.

Given that we live in an era of radical change, far greater than in any past age, there is considerable tension between what we can achieve with technology and instinctive conservatism. People organize to resist every prospective change that they later take full advantage of and approve of, and the acts of government employees are just one of the better reported parts of this urge to stasis. All meaningful progress happens against the will of the grumbling masses and their elected leaders, yet is instantly adopted as the new stasis the moment that people can buy the products, or the therapies, or the activities. In advocacy for rejuvenation research and the medical control of aging it is quite frustrating to listen to opponents who, were they lucky enough to be born later, would be uncritically accepting of the medicine they oppose. Were they unlucky enough to be born earlier, they would have railed against gene therapy, or heart surgery, or other important past advances that are now proudly accepted as proof of prowess in technology. It has everything to do with change and nothing to do with the matter at hand.

Moving away from opposition to progress, the flip side of the urge to stasis is support for the present situation, even if absolutely untenable. In the case of aging we are faced with a medical condition that kills 100,000 people every day, while hundreds of millions are unable to support themselves, or in chronic pain, or possessed of a heart or a mind no longer fully functional. The conservative response to that is to do nothing other than try to better organize this vast and ongoing dying: to accept it as-is, to accept the enormous waste and expenditure, pain and suffering. It is all about coping, not fixing. You'll find no sign of anything involving change for the better, or change at all for that matter, in the story presented by the government here:

White House Conference on Aging (WHCOA)

As expected, there was next to nothing at the WHCOA about aging research. At an early (April) local WHCOA meeting in Phoenix, the director of the National Institute on Aging - Dr. Richard Hodes - spoke a few minutes about the genetics of Alzheimer's, and the possibility and need for its early detection. But apparently that was about it.

Fact Sheet: The White House Conference on Aging

The HHS Health Resources and Services Administration announced that it will develop an Alzheimer's Disease and Related Dementias training curriculum next year to build a health care workforce with the necessary skills to provide high quality dementia care and ensure timely and accurate detection and diagnosis of dementia.

Care, detection, diagnosis. No mention of treatment. This is representative of all of the documents resulting from this initiative. You'll see the same in the health sections of aging.gov if you care to look. The lesson to take away here is that change for the better will never emerge from the normal machinations of government. Change comes from outside the system. If you are one of those who wants the government to participate and lead, then you have to accept that the only way to make that happen is for the research strategies you favor to become the mainstream of research or a popular cause for millions. The people who guide the direction of resources in representative governments are the very last to turn their eyes to any sort of new project.

PERSUASION AS ACTIVISM FOR REJUVENATION RESEARCH
https://www.fightaging.org/archives/2015/07/persuasion-as-activism-for-rejuvenation-research.php

We stand at the dawn of a new age of medicine, an era in which the causes of aging will be treated and reversed, leading ultimately to indefinite healthy life spans, as many years as want. The transition from where we are today to the availability of effective therapies to prevent and cure the manifestations of degenerative aging will be very rapid in the context of the overall history of medicine, but still a matter of years and decades of hard work and persuasion for those of us living through it. At the large scale funding and progress in medicine follows popular support for the end goal, and at the present time we're still in the late opening stages of persuading the world that, yes, treating aging is a good thing and we should get right on with it. It remains the case that the average fellow in the street is suspicious, indifferent, or even hostile to the idea of living longer through medical science.

This will no doubt be seen as inexplicable by our exceedingly long-lived descendants, who will never suffer age-related disease and look back on our era in the same way as we look back on the poverty, disease, and suffering of Dickensian London. But we must play the hand we are dealt, and we are faced with a task of persuasion in order to bring enough people around to the idea that we should be treating aging. Given the number of deaths caused by aging, far more than any other medical condition, treating it should in fact be the primary purpose of the medical community rather than a field that receives little funding and notice - but again, all too few people agree. The more that we speak out in favor of greater funding and more effective approaches to treating aging as a medical condition, the faster we move towards that end goal.

Every cultural movement is a tapestry of efforts, woven from the initiatives at the grassroots to the backroom conversations of venture capitalists, and ideas flow here and there very freely in our highly connected society: a diffuse conversation about medicine and aging that anyone can join to have their say. The more that we talk about this topic, the more that people will think on it. Some of them will also join in. Over the past decade I have seen an acceleration in the number of new faces and new initiatives: the size of the community of people in favor of medicine to treat aging is increasing, and a tipping point lies somewhere ahead, much closer than when I first had this notion of writing about the science of aging and the prospects for healthy longevity.

We can all write, we can all talk to our friends, and we can all distribute our thoughts on the matter far and wide thanks to the internet. As ever more of us choose to do this, we help to build the future consensus on the treatment of aging. One day not so far from today, it will be obvious to the fellow in the street that aging itself falls into the same category as cancer and Alzheimer's disease, and of course it is a good thing that researchers are working towards a cure for aging, and it won't be unexpected to see people raising funds for those research programs in exactly the same way that they do for cancer today. So keep right on helping: talk to your friends, write online, say something about aging and longevity. It makes a difference.

Transhumanism Is Booming and Big Business Is Noticing

I recently had the privilege of being the opening keynote speaker at the Financial Times Camp Alphaville 2015 conference in London. One thing I noticed at the conference was the increasing interest in longevity science--the transhumanist field that aims to control and hopefully even eliminate aging in the near future. Naturally, everyone has a vested interest in some type of control over their aging and biological mortality. We are, at the core, mammals primarily interested in our health, the health of our loved ones, and the health of our species. But the feeling at the conference - and in the media these days too - was more pronounced than before.

As a transhumanist, my number one goal has always been to use science and technology to live in optimum health indefinitely. Until the last few years, this idea was seen mostly as something fringe. But now with the business community getting involved and supporting longevity science, this attitude is inevitably going to go mainstream. I am thrilled with this. Business has always spurred new industry and quickened the rise of civilization.

A matter of chance

Rejuvenation biotechnologies wouldn't just cure billions of people of age-related diseases, but would prevent the life of severely injured, sick and disabled people from getting considerably worse with age; and on top of that, anti-ageing therapies have the potential to enable them to live long enough to see the day when the condition that has been afflicting them for so long can be cured. They could see the day they can walk again, and undo the damage done to their only chance, which will hopefully last for yet very long. In the end, it isn't all that wrong to say that we have only one chance; that's exactly the reason why we shouldn't take any chances with it.

For Life's Sake, Join the Movement for Indefinite Life Extension

The number of demonstrations and rallies designed to drive awareness of the cause have been increasing. These brave and vital showings of leadership are pivotal in reaching the next levels of awareness and willingness to step forward for this cause. Because of these people, more around the world find the courage to take their first steps in support of this cause. To find a hero in this cause, you need not look far; there are whole groups of them, and you can take your pick.

We don't want to die. Sitting it out and letting others handle it will get us all killed. Time is ticking. This isn't about seeing if we can reach a goal; this is about having it within us to understand that we can achieve this in time for us and the people we know. Achieving indefinitely healthy longevity is about the expedition of this goal as a movement.

LATEST HEADLINES FROM FIGHT AGING!

A REVIEW OF THE USE OF C. ELEGANS IN AGING RESEARCH
Monday, July 13, 2015
https://www.fightaging.org/archives/2015/07/a-review-of-the-use-of-c-elegans-in-aging-research.php

A great deal of early stage research into the mechanisms of aging takes place in very short-lived species such as the nematode worm Caenorhabditis elegans, and here researchers review the use of this species in the laboratory. Why research aging in species very different to our own? Because the economic advantages of being able to study a full life span of many individuals in a short time and at a low cost, coupled with a mature technology platform for genetic manipulation and analysis, more than offset the hurdles and dead ends that arise due to biological differences between nematodes and mammals. The fundamental mechanisms of metabolism and their relationship with aging are in fact surprisingly similar between very diverse species, a fortunate happenstance that speeds exploratory research.

Over a century ago, the zoologist Emile Maupas first identified the nematode, Rhabditis elegans, in the soil in Algiers. Subsequent work and phylogenic studies renamed the species Caenorhabditis elegans or more commonly referred to as C. elegans; (Caeno meaning recent; rhabditis meaning rod; elegans meaning nice). However, it was not until 1963, when Sydney Brenner, already successful from his work on DNA, RNA, and the genetic code, suggested the future of biological research lay in model organisms. Brenner believed that biological research required a model system that could grow in vast quantities in the lab, were cheap to maintain and had a simple body plan, and he chose the nematode C. elegans to fulfill such a role.

Why has C. elegans been used so successfully for aging research? What would make an organism suitable for aging research? The ability to easily and cheaply grow large quantities of worms in the lab is very helpful for aging research, especially when identifying long-lived mutants. C. elegans also have a relatively short lifespan (average approximately 17 days at 20 °C), and the lifespan is largely invariant. The latter allows for identification of mutants that shorten or lengthen average lifespan by as little as 10-15% and still be of statistical significance. Additional benefits of using C. elegans include that the entire genome is sequenced and annotated, the availability of an RNAi library comprising approx. 80% of the genes in the genome, the ease of generating transgenic strains and the recent development of gene-targeting approaches. This has allowed for extensive forward and reverse genetic screens for genes that modulate lifespan.

Another advantage working with C. elegans for studying the aging process is that the lifespan assay is straightforward, which allows for large numbers of worms to be assayed in a single experiment. Therefore, statistical significance can be tested in addition to the analysis of mortality rates. Together, these techniques allow one to comprehensively survey the worm genome for genes that modulate lifespan. This has led to the identification of more than 200 genes and regimens that modulate lifespan in C. elegans and revealed evolutionarily conserved pathways that modulate lifespan. Therefore, the combination of the short, invariant lifespan, ease of assays, ample genetic, molecular and genomic tools, and evolutionary conservation has allowed C. elegans to develop into a premiere model system for aging research.

P53 AND RAPAMYCIN HAVE ADDITIVE EFFECTS ON MTORC1
Monday, July 13, 2015
https://www.fightaging.org/archives/2015/07/p53-and-rapamycin-have-additive-effects-on-mtorc1.php

mTOR is a hot topic in aging research these days, at least for those parts of the community seeking to develop drugs capable of modestly slowing the aging process. As a goal this is something that I think isn't really worth the time and money poured into it, not when there are other paths ahead based on repairing the causes of aging, capable of producing the far better outcome of rejuvenation and restored health. Persuading the research community on this topic is an ongoing project, led by organizations such as the SENS Research Foundation.

Rapamycin is one drug candidate shown to slow aging in laboratory species, but it affects both mTORC1 and mTORC2 to cause beneficial and harmful effects in equal measure - it isn't something you'd want to take if you had any choice in the matter. Thus researchers focus on intervening in mTORC1, and rapamycin should probably be considered a tool for investigation rather than an actual drug candidate. Like many areas of research into metabolism and aging, this is also relevant to cancer research:

mTOR is a serine/threonine kinase found in two complexes, mTORC1 and mTORC2. mTORC1 coordinates cell growth and metabolism in response to environmental stresses, nutrient and energy levels, growth factors and other conditions. Rapamycin extends life span of wild type mice, possibly through cancer suppression since mTORC1 signaling is often dysregulated in cancer cells. Dietary rapamycin also ameliorated general aging in wild type mice for most, but not all studies. Rapamycin also extended life span for lower organisms that do not die from cancer suggesting that rapamycin suppresses general aging in addition to cancer. Thus, rapamycin appears to suppress mTORC1-mediated oncogenesis and possibly general aging.

p53 is a transcription factor with broad biological function that is best known for suppressing tumors in humans and mice by inducing cell cycle arrest, apoptosis and senescence in response to a variety of stresses. p53 inhibits mTORC1 and thus suppresses mTORC1-driven cell growth in response to cellular stresses like DNA damage.

We provide three lines of evidence that support the notion that p53 and rapamycin are additive. First, p53 enabled enterically targeted rapamycin to extend life span in mice. Second, p53 facilitated the ability of rapamycin to suppress radiation-induced senescence-associated secretory phenotype in human cells. Third, p53 enabled rapamycin to elevate amino acid and citric acid levels in mouse embryonic stem cells. Thus, there appears to be an augmentative relationship between p53 and rapamycin.
We suggest that p53 and rapamycin blunt mTORC1 activity through different pathways to result in this additive relationship.

This contention is relevant to the use of mTORC1 inhibitors as anti-cancer therapeutics since p53 is mutated or dysfunctional in most cancers. mTORC1 inhibitors might be most effective early in the oncogenic process, before p53 is mutated. Our previous results support this possibility since we found that rapamycin suppressed the development of tumors with wild type p53. High levels of mTORC1 inhibitor might be needed to overcome cancer with p53-null mutations. Yet for those p53-dysfunctional cancers that have a functional p53 protein, mTORC1 inhibitors coupled with p53 enablers such as nutlin could be a powerful combination allowing a lower dose for each.

A RECENT INTERVIEW WITH AUBREY DE GREY OF THE SENS RESEARCH FOUNDATION
Tuesday, July 14, 2015
https://www.fightaging.org/archives/2015/07/a-recent-interview-with-aubrey-de-grey-of-the-sens-research-foundation.php

A recent interview with Aubrey de Grey of the SENS Research Foundation touches on a range of topics relevant to progress in the development of rejuvenation therapies:

I got involved in gerontology about 20 years ago when I discovered that hardly any biologists were trying to do anything about aging. Until then I had always assumed that everyone understood that aging is the world's worst problem and that defeating it was a major focus of biology. I co-founded SENS Research Foundation (and the Methuselah Foundation before it) because I saw that the most promising source of funding for this sort of long-term translational work was philanthropy, rather than government funding or the private sector. We have about a dozen different projects going on, which span most of the areas that have been described in my publications, out of the five million that we spend each year, most goes on these research projects, two of them in our center in California, and the rest in various institutes and universities across the USA (plus one in the UK). We also spend some money on outreach and education.

To me, gerontology is the study of aging as a basic science - the quest to understand aging better and better. But what SENS Research Foundation does is to try to manipulate aging - to postpone it better and better. And promising advances in one of those quests are not necessarily promising in the other one. So the most promising developments in gerontology would include things like the finding that calorie restriction doesn't work much in monkeys, or that naked mole rats protect themselves from cancer using long-chain hyaluronic acid; the most promising advances in engineering negligible senescence would include things like the removal of amyloid in Alzheimer's patients using vaccination, or the protection of cells from oxidised cholesterol by giving them a bacterial enzyme that breaks it down.

Everyone in the field knows that longevity is a side-effect of health: if you increase healthspan (i.e. you postpone the ill-health of old age), you will similarly increase lifespan. Everyone in the field also knows that there is no good age to die - that however much we succeed in postponing age-related disease and disability, we will always want to postpone it more. But they also know that politicians and the general public are petrified of thinking rationally about all this, because aging has them in such a tight psychological stranglehold that all they want to do is put it out of their minds - so they feel forced into this downright dishonest kind of language that implicitly deprecates those few people who dare to be honest about the fact that the longevity side-effect of postponing ill-health is a side-effect that we should welcome. They feel that if they were to endorse the desirability of much longer lifespans, they would cause a backlash in political circles and a reduction in research funding. I'm quite sure they are wrong, and that if the whole field were as honest about all this as I've always been then it would have far more money by now - but there seems to be no way to persuade most of my colleagues of that.

A NOVEL CONTRIBUTION TO AGE-RELATED HEARING LOSS
Tuesday, July 14, 2015
https://www.fightaging.org/archives/2015/07/a-novel-contribution-to-age-related-hearing-loss.php

Researchers here uncover a novel mechanism that contributes to age-related hearing loss, involving changes in nerve cell communication in older animals. At the present time, much of the work on potential ways to treat loss of hearing with age is focused on hair cells and their regeneration. Some progress has been made on this front, with mouse studies demonstrating partial recovery of hearing through restoration of hair cell populations. It will be unfortunate if it turns out that this approach isn't sufficient on its own to form an effective therapy, but the presence of another important mechanism would explain the partial results seen to date:

Conventional wisdom has long blamed age-related hearing loss almost entirely on the death of sensory hair cells in the inner ear, but new information about the workings of nerve cells suggests otherwise. Researchers have verified an increased number of connections between certain sensory cells and nerve cells in the inner ear of aging mice. Because these connections normally tamp down hearing when an animal is exposed to loud sound, the scientists think these new connections could also be contributing to age-related hearing loss in the mice, and possibly in humans. "The nerve cells that connect to the sensory cells of the inner ear are known to inhibit hearing, and although it's not yet clear whether that's their function in older mice, it's quite likely. If confirmed, our findings give us new ideas for how physicians may someday treat or prevent age-related hearing loss."

The new research builds on the knowledge that inside the ear lies a coiled row of sensory cells responsible for converting sound waves into electrical signals sent through nerve cells to the brain, which processes and tells animals what they "hear." Each of those nerve cells is like a one-way street, taking signals either from the ear to the brain or vice versa. The nerve cells that take signals to the ear are known to turn down the amplification provided by outer hair cells when an animal is, for example, exposed to a noisy environment for an extended period of time. But studies over the last decade have suggested that changes over time also occur in the connections between hair cells and the nerve cells to which they are attached.

The researchers painstakingly recorded electrical signals from within the inner hair cells of young and old mice. They found that the incoming nerve cells were indeed active and that their activity levels correlated with the animals' hearing abilities: The harder of hearing an animal was, the higher the activity of its incoming nerve cells. "These nerve cell connections seem to be reverting back to the way they worked during early development before the animals' sense of hearing was operating. We don't know why the new connections form, but it might be as simple as a lack of competition for space once the outgoing nerve cells have retracted."

THERE ARE ALWAYS THOSE WHO TRY TO TELL US THAT GREATER LONGEVITY WILL BE A DISASTER
Wednesday, July 15, 2015
https://www.fightaging.org/archives/2015/07/there-are-always-those-who-try-to-tell-us-that-greater-longevity-will-be-a-disaster.php

There are always those who try to argue that increasing human healthy life span would be an economic disaster. I would have thought this a hard view to justify to oneself given centuries of economic growth walking hand in hand with greater life expectancy, but many people prioritize the present unsustainable structure of economic entitlements in Western societies more highly than any number of lost and crippled lives. In their eyes the machine must continue exactly as it is, regardless of the deaths and suffering that pays for it. This is the small-c conservative impulse at work, the tendency for people to support and defend the present status quo, no matter how ridiculous it might be, and no matter how or when it came into being. But the world will change in response to new capabilities in medicine, and political and economic systems that cannot possibly work will fall. They are far less important than better and longer lives for ordinary people.

Change is not disaster. It is progress. Why receive entitlements if you are old but not frail? Why retire if you don't have to? Why think of someone in their 60s and 70s as less capable than someone in their 30s when that is no longer the case? The purpose of research into extended longevity is to prevent the frailty and illness that stops people from being able to support themselves. Entitlements and forced wealth transfers have no place in that near future world, regardless of what you might think of them today.

Most of us think of longevity as a gift, a blessing, a sign of social progress. Gordon Woo thinks of it as a catastrophe. Woo is one of the world's best-respected "catastrophists," and helps insurers and reinsurers calculate the likelihood of disastrous earthquakes, hurricanes, droughts, terrorist attacks, financial crises, and other hazards. Woo's major preoccupation these days is the risks posed by people living longer. Unlike some futurists, Woo does not believe the aging of the population is going to plateau any time soon - not in an era when you'll be able to replace more of your spare parts and take the drugs that work best for your personal genome. And that could have huge implications in the coming decades, as civilizations struggle to meet the medical and financial needs of their elders.

MG: Can you explain why longevity is bad?

GW: We're focusing on the pension retirement sector, and it's really underfunded in terms of its provision for increasing lifespan in the decades ahead. One reason is that when it comes to making provisions for longevity instead of ecological or geological catastrophes, regulators tend to be fairly light of touch. There's good reason for this. If a corporation seems to have a black hole in its pension fund, it may not be a good policy to force the corporation to pump more money into the fund while it's going through hard times, because that very act could draw the corporation into insolvency. That's why regulators, even if they spot the problem with the pension fund, are often reluctant to force measures to remedy the situation. Often the thinking is, times will get better, corporations will get out of trouble, hopefully everything will be rosy in the future. But that will not be the case.

MG: How much longer are people living? Is this trend going to accelerate going forward?

GW: There is one view within the actuarial community that it might be leveling out - medical discovery is plateauing, it's getting harder to discover new drugs, there are diminishing returns, that kind of thing. But that perspective doesn't allow for the expansion of research into whole new territories such as regenerative medicine and anti-aging.

ULTRASOUND CAN ACCELERATE SKIN HEALING IN THE ELDERLY
Wednesday, July 15, 2015
https://www.fightaging.org/archives/2015/07/ultrasound-can-accelerate-skin-healing-in-the-elderly.php

Not all approaches to changing the behavior of cells so as to spur greater regeneration must necessarily involve drugs. Here researchers demonstrate that ultrasound can partially compensate for age-related deficiency in skin healing, and catalog some of the cellular biochemistry involved. This isn't a case of fixing the proximate cause of faltering wound healing, a decline in one specific type of cell signaling, but rather activating another mechanism that can act as a substitute to some degree. As the publicity materials note, deploying this treatment to the clinic should not be too much of a challenge given the present widespread use of ultrasound for other purposes:

Chronic skin healing defects are one of the leading challenges to lifelong wellbeing, affecting 2-5% of populations. Chronic wound formation is linked to age and diabetes and frequently leads to major limb amputation. Here we identify a strategy to reverse fibroblast senescence and improve healing rates.

In healthy skin, fibronectin activates Rac1 in fibroblasts, causing migration into the wound bed and driving wound contraction. We discover that mechanical stimulation of skin with ultrasound can overturn healing defects by activating a calcium/CamKinaseII/Tiam1/Rac1 pathway that substitutes for fibronectin-dependent signaling and promotes fibroblast migration. Treatment of diabetic and aged mice recruits fibroblasts to the wound bed and reduces healing times by 30%, restoring healing rates to those observed in young, healthy animals. Ultrasound treatment is equally effective in rescuing the healing defects of animals lacking fibronectin receptors, and can be blocked by pharmacological inhibition of the CamKinaseII pathway. Finally, we discover that the migration defects of fibroblasts from human venous leg ulcer patients can be reversed by ultrasound, demonstrating that the approach is applicable to human chronic samples.

By demonstrating that this alternative Rac1 pathway can substitute for that normally operating in skin, we identify future opportunities for management of chronic wounds.

GRASSROOTS POLITICAL ADVOCACY FOR LONGEVITY IN EUROPE
Thursday, July 16, 2015
https://www.fightaging.org/archives/2015/07/grassroots-political-advocacy-for-longevity-in-europe.php

Here is an example of grassroots advocacy for longevity science in Europe, where single-issue political parties are a viable approach to advancing a cause, unlike the case in the US. It is always heartening to see any one person step out of the crowd to make a stand and say that, yes, it is very important that research into treating aging as a medical condition is funded and supported. Success comes when enough people do this: any movement is just a matter of many individuals making this choice and giving time and money to building the future they want to see.

There are a number of small single-party efforts in various European countries, and many of them collaborate through the International Longevity Alliance, a network of activists looking to make a better future. As of yet this is still a small group, even taken together as a whole, but the fact that it exists at all is a sign that the tide is rising, with ever more people realizing that there are realistic prospects for the treatment of aging and elimination of age-related disease. The efforts of these activists are the seeds of much larger initiatives yet to come, and are to be commended:

In our new LIFEMAG community series, we interview activists throughout the world looking to take life extension ideas from the radical to the mainstream. In this first instalment, Valentina Lencautan speaks to Felix Werth, a biochemistry student at Potsdam University, who has founded Germany's first and only life extension focused political party - the Partei für Gesundheitsforschung (Party for Health Research). At the party's weekly meeting, Felix explains how the party was formed six months ago in the hope of attracting enough members to spread the word about life extension, and increase the German government's investment in aging research.

What made you get into life extension activism?

It was seeing the work of SENS and interviews with Aubrey de Grey among others. I was inspired so much that I decided to study to become a biochemist myself. I was thinking about what I could do for the cause of life extension, and thought starting a political party was a good way to raise awareness, and also encourage the German government to invest more in aging research. The current budget of the German government is over €300bn, so if just one per cent of that was invested in aging research, that would be €3bn.

Is there a big support base for life extension in Berlin?

I am afraid we are still a very small group, but I hope that will change. To be able to participate in the elections, the party needs about 400 members, and we're still some way off achieving that. I try to tell people that this matter concerns their lives, that it's not just about living a healthy lifestyle. Nowadays people are flooded with information about what they should eat and the exercise we should do. Many perceive us as yet another health advisor who is trying to tell them how they should live. Many find it difficult to understand what the SENS concept is, that it is about repairing the body and rejuvenation. Others just do not believe it is possible. It is a matter of convincing people that it can be a reality.

So you are campaigning not for just more funding, but also for the SENS method in research as well?

The SENS method is the best one there is at the moment, but I would leave this kind of decision to the scientists. The party's main purpose is to find the money to be invested into research. It is all about finding therapies for the diseases of old age. If we were to receive more funding, research would evolve so much faster. It is simple logic.

A MERGING OF ADVOCACY FOR TECHNOLOGICAL CONVERGENCE AND FASTER MEDICAL RESEARCH
Thursday, July 16, 2015
https://www.fightaging.org/archives/2015/07/a-merging-of-advocacy-for-technological-convergence-and-faster-medical-research.php

Today I thought I'd point out an interesting take on advocacy for faster progress in research from an organization called The Cure is Now. There is a great deal of frustration with the slow pace of medical research, the consequence of excessive regulation in that field. The regulatory cost of developing treatments has grown enormously over the past few decades, to no good end, and as a result far less new medicine is actually making it out of the labs, despite the enormous and rapid progress in biotechnology taking place. One manifestation of this frustration is the existence of organizations such as Faster Cures, Tomorrow's Cures Today, and Breakout Labs, all of which take somewhat different approaches to trying to break the logjam, ranging from straightforward lobbying to venture philanthropy.

The Cure is Now has yet another view on the best way forward to speed up the development of better therapies and new cures, its focus being on accelerating the coming technological convergence in fields such as genetics, computing, and molecular nanotechnology. Once further along present trends in this direction will result in entirely new paradigms and platforms for medicine based on complete control over cells and the replacement of biological components at all scales with more effective and more robust machinery. These are explicitly transhumanist goals, and more people are thinking in those terms these days, given the popularizing of modern variants of the technological singularity concept, now having more to do with accelerating progress and next generation technology than the original ideas from Vinge specifically related to artificial intelligence.

The Cure is Now prose is all too breathless, and veers between overly general and too specific, but that is something that improves with organizational growth and experience. I can't say that I was any good when first starting out. Overall this looks like a small group that is doing more than just talking about things, also seeking to fund specific useful areas of research, and that is commendable. You can write however you want to write if you are also delivering money to research efforts. The future is built of many such modest initiatives, a tapestry of individual choices, people trying to make a better future by improving medicine and its support technologies:

The Cure Is Now is a national non-profit organization organized by people who share a common bond. Having their lives personally affected by horrible diseases, this group came together out of desperation over the fact that there does not seem to be a simple answer as to how, when and if there will be reliable, robust, and clear cut cures to the long list of incurable diseases that kill loved ones every day.

There are many incurable diseases that need to be addressed. The Cure Is Now is using what it calls the Root Level Approach to solving the problems by facilitating groups of individuals who will work together to achieve this goal. By employing a Committee on Advanced Technology, Medical Advisory Board and a Science Advisory Board to explore radically advanced, emerging technologies, The Cure Is Now hopes to accelerate speculative and emerging technologies in order to lead to the event known as The Singularity.

The driving forces behind The Cure Is Now are the realization of something known as the technological singularity. There is an event that will change the world more so than major breakthroughs like the Internet, industrialization, democracy, flight, or other paradigm shifting social evolutions. This event known as the technological singularity will bring forth changes for human kind that will address some of our most fundamental needs in ways that have never been before possible.

Research has shown that several groups of thus far so called "incurable" diseases can be potentially addressed in ways that have never before been conceived of. Today The Cure Is Now seeks to address the very concept of attacking these diseases with several new emerging and speculative technologies. So if you're looking for an explanation as to why The Cure Is Now does not target one simple disease but rather several of them, it is precisely because we feel that the way to cure a disease is not necessarily through the conventional pharmaceutical and medical methods used thus far. Rather, a whole slew of new and radically advanced technologies will be converged and applied in order to invent new methods of finding cures. The Cure Is Now subscribes to what we call the root level approach. The root level approach quite simply states that a convergence of several new advanced technologies will address the hurdles in thus far incurable diseases: artificial general intelligence; molecular nanotechnology; biotechnology; brain-machine interfaces and neuroscience, networks and supercomputing; and genomics.

MORE ON AGING RESEARCH AT THE BUCK INSTITUTE
Friday, July 17, 2015
https://www.fightaging.org/archives/2015/07/more-on-aging-research-at-the-buck-institute.php

Here is a second in a series of popular press articles on the work of the Buck Institute for Aging Research, this one focused on studies of the mechanisms of aging in nematode worms:

The genes of Caenorhabditis elegans, a 1 millimeter-long, soil-dwelling roundworm or nematode, resemble those of people. Its genome - complete set of DNA with about 19,000 protein-coding genes - differs from ours in architecture but has some 60 percent protein conservation, where proteins expressed by the genes have similar shapes and functions. With a normal lifespan of just 20 days, C. elegans offer scientists at Novato-based Buck Institute for Research on Aging a keen glimpse of the aging process. A C. elegans worm has only 959 cells, each conveniently transparent when viewed through a microscope.

In 1993, Cynthia Kenyon, a biochemist and former faculty member at University of California, San Francisco with a Ph.D. from MIT, discovered that partially disabling the daf-2 gene which encodes the insulin-like growth factor receptor in C. elegans doubled its healthspan. It was a breakthrough. Like worms, humans have genes that control insulin-like growth factor. Since then she genetically tinkered further to give some worms a sixfold lifespan.

Scientists in laboratories at Buck continue to push C. elegans for answers to human aging, drawing on Kenyon's lead. Kathleen Dumas, post-doctoral research fellow for the past two years in Buck's Lithgow lab, also studies the worms. Dumas explores protein homeostasis in the worms. "With age, we have a breakdown in the normal maintenance of cells," Dumas said. "Protein folding can change with age." She is looking for genetic tools or drug molecules that can be used to shift protein misfolding. "We don't know that protein misfolding is causing aging. It could be the other way," that aging causes misfolding. "We see that it correlates. This is one of the bad things. If we can prevent protein misfolding, that could be one way to improve cellular functioning with age."

Cellular cleanup mechanisms and gene expression such as synthesizing protein change with age, Dumas said. Both processes relate to protein homeostasis inside cells. "Parkinson's and Alzheimer's are probably directly caused by aggregates of proteins that no longer do what they should," she said. "Proteins are the machines doing everything in our cells. If we have faulty parts or the wrong number of parts, those machines will break down. You get chaos - functional decline."

RESVERATROL AS A CAUTIONARY TALE
Friday, July 17, 2015
https://www.fightaging.org/archives/2015/07/resveratrol-as-a-cautionary-tale.php

For those who haven't yet got the message, the article linked here points out just how little came of resveratrol as a drug candidate and sirtuin research as a whole from the past decade. Resveratrol and the study of sirtuins were hyped up at the time, as I'm sure many of you recall, and yet nothing came of it beyond a little more knowledge of cellular metabolism. Sirtuins do not have any meaningful influence on aging from the perspective of producing therapies and neither does resveratrol. The hype resulted from a confluence of the tendency for venture investment to talk up a position (in the company Sirtris, acquired for more than 700 million in the end, money written off by the acquirer since nothing of practical use ever came from it), and the "anti-aging" marketplace finding yet another set of potions its members could market to the gullible. A lot of resveratrol was sold, and many people who really should have known better bought some.

Whenever a new drug candidate emerges with claims that it allegedly slightly slows the aging process, the first thing you should think of is resveratrol, and be wary of hype driven by the profit motive. Resveratrol was just the latest in a line of hyped products allegedly providing benefits to health in aging, and in fact doing nothing of any significance other than helping some people to find profits. Mining the natural world for compounds that can alter the operation of metabolism has shown itself incapable of reliably producing results that matter when it comes to aging: decades of work on this and nothing to show for it but the continued ability to sell useless products to people who hope for something that works.

There is only one useful road ahead here when it comes to aging and health. It is the construction of new biotechnologies that deliberately and usefully repair the cellular damage that causes aging. Don't alter metabolism, instead fix it by removing the dysfunction that causes it to run awry in a careful, targeted way. The future is clearance of damaged cells, gene therapies to repair mitochondrial DNA, manufactured enzymes that break down specific forms of persistent metabolic waste, and so on - a world away from screening random compounds from plants in the hope that they will do more good than harm.

Resveratrol is a compound that gained a lot of notoriety in the mid-2000's as sort of a multipurpose pro-health molecule. In its heyday, it spawned companies and a plethora of enthusiastic articles that recommended binging on resveratrol-containing foods as an all-purpose health enhancement. Interest has since waned on this compound, but it's worth revisiting the story to see how an exciting, trendy scientific discovery can lose steam when scientists better understand its limitations. A first hint of Resveratrol's pro-health effects came in 2003 out of the lab of David Sinclair, a young investigator at Harvard. Sinclair's lab found that resveratrol could extend lifespan in yeast. The extension was thought to be dependent on the protein Sir2, the founding member of a family of related proteins called sirtuins. The idea that small molecules could be used to extend healthspan was gaining excitement and attracting funding. A year later, Sirtris went public, eventually being bought up by pharma giant GlaxoSmithKline. The resveratrol supplement industry grew.

However, later reports led to questioning resveratrol's benefits. Work out of the lab of Linda Partridge, a well-respected Drosophila researcher, was unable to reproduce earlier findings of lifespan extension in Drosophila and produced only variable effects in C. elegans. There has also been a broader controversy over the role of resveratrol's reported target SIRT1. A major stain on the field came in 2012, when resveratrol researcher Dipak Das was fired from UConn for allegedly committing 145 instances of scientific fraud including "fabrication and falsification of data". Much of Das' work formed the basis for supposed cardioprotective benefits of resveratrol. As a result, resveratrol's efficacy for this application is now in serious doubt.

But even before the Das controversy, there were indications that people in the know had cooled on resveratrol related formulations as therapeutics, possibly due to inherent limitations with the compound. One of the co-founders of Sirtris left the company in 2011, and GlaxoSmithKline eventually shut down Sirtris and folded it into its broader business. This diminished industry interest in resveratrol may stem from two unfortunate issues: 1) research suggesting resveratrol does not act via SIRT1 makes it difficult to develop resveratrol into a drug; and 2) resveratrol is rapidly degraded by the liver after ingestion, making it naturally a poor drug. The first is an even bigger problem than it seems because FDA approval of new drugs requires knowing their mechanism of action. The second is a problem because it means it's difficult to increase the levels of resveratrol in the body by taking a pill, and medicines usually need to be administered by pill for average patients to be able to use them.

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