Considering Pan-mTOR Inhibitors as Alternatives to Rapamycin

For a number of years now, mechanistic target of rapamycin (mTOR) has been the focus of a fair amount of research into aging. Goals include gaining a better understanding of the way in which metabolism determines natural variations in longevity, and also establishing means by which the pace of aging might be modestly slowed via long-term pharmaceutical alteration of metabolic processes. I don't consider this to be the most effective way forward for longevity science, but evidently a lot of people do. mTOR appears to be a factor in a range of genetic and other interventions shown to slow aging to varying degrees in laboratory animals, but for most of these so many changes take place in cellular biochemistry that it remains a challenge to talk definitively about root causes or most important mechanisms.

So far the search for drug candidates to target mTOR has produced few if any outstanding new leads. Rapamycin is the starting point, and has been shown to extend life span in mice, but it has side-effects that make it undesirable for widespread use in humans. Researchers have been exploring the expanding suite of rapalogs, drugs with similar structures and effects, but so far nothing has jumped to the fore by virtue of a large enough improvement to demand immediate clinical development. mTOR forms two complexes in the course of interactions relevant to aging, mTORC1 and mTORC2. There is a school of thought that suggests the problems inherent in rapamycin and similar compounds arise because they affect both of these complexes. There is evidence to suggest that targeting mTORC1 while leaving mTORC2 alone would capture beneficial outcomes without many of the problem side-effects - but easier said than done with pharmaceuticals given the tools to hand. The real issues in the biochemistry are also probably more complex than this simplistic view of the situation.

The paper linked below is characteristic of continued exploration of pharmaceutical databases in search of better options, as well as the increasing complexity of the underlying theory that steers this exploration. The biochemistry of aging, the intricacy with which it progresses from moment to moment, is enormously complex. The paper is also characteristic of an increasing interest in cellular senescence in all areas of the aging research community. With the proof that removal of senescence cells extends life in mice, and increasing evidence for the role of senescent cells in specific age-related diseases, researchers now have to fit these findings into the many and varied existing views of aging, or give senescence greater prominence where already present. In the case of mTOR, researchers demonstrated last year that mTOR inhibition appears to slow the approach of cells towards replicative senescence, the state that occurs at the Hayflick limit on cell replication, which is one of the reasons why it appears here as a yardstick for measuring the effects of alternatives to rapamycin.

Gerosuppression by pan-mTOR inhibitors

Rapamycin slows down aging in yeast, Drosophila, worms, and mice. It also delays age-related diseases in a variety of species including humans. Numerous studies have demonstrated life extension by rapamycin in rodent models of human diseases. The maximal lifespan extension is dose-dependent. One explanation is trivial: the higher the doses, the stronger inhibition of mTOR. There is another explanation: mTOR complex 1 (mTORC1) has different affinity for its substrates. For example, inhibition of phosphorylation of S6K is achieved at low concentrations of rapamycin, whereas phosphorylation of 4EBP1 is insensitive to pharmacological concentrations of rapamycin. Unlike rapalogs, ATP-competitive kinase inhibitors, also known as dual mTORC1/C2 or pan-mTOR inhibitors, directly inhibit the mTOR kinase in both mTORC1 and mTORC2 complexes.

In cell culture, induction of senescence requires two events: cell cycle arrest and mTOR-dependent geroconversion from arrest to senescence. In proliferating cells, mTOR is highly active, driving cellular mass growth. When the cell cycle gets arrested, then still active mTOR drives geroconversion: growth without division (hypertrophy) and a compensatory lysosomal hyperfunction (beta-Gal staining). So senescence can be caused by forced arrest in the presence of an active mTOR. Senescent cells lose re-proliferative potential (RPP): the ability to regenerate cell culture after cell cycle arrest is lifted. Quiescence or reversible arrest, in contrast, is caused by deactivation of mTOR. When arrest is released, quiescent cells re-proliferate. In one cellular model of senescence (cells with IPTG-inducible p21), IPTG forces cell cycle arrest without affecting mTOR. During IPTG-induced arrest, the cells become hypertrophic, flat, SA-beta-Gal positive and lose RPP. When IPTG is washed out, such cells cannot resume proliferation. Loss of RPP is a simple quantitative test of geroconversion. Treatment with rapamycin during IPTG-induced arrest preserves RPP. When IPTG and rapamycin are washed out, cells re-proliferate.

Recently, we have shown that Torin 1 and PP242 suppresses geroconversion, preventing senescent morphology and loss of RPP. In agreement, reversal of senescent phenotype was shown by another pan-mTOR inhibitor, AZD8085. Pan-mTOR inhibitors have been developed as cytostatics to inhibit cancer cell proliferation. Cytostatic side effects in normal cells are generally acceptable for anti-cancer drugs. However, cytostatic side effects may not be acceptable for anti-aging drugs. Gerosuppressive (anti-aging) effects at drug concentrations that are only mildly cytostatic are desirable. Pan-mTOR inhibitors differ by their affinity for mTOR complexes and other kinases. Here we studied 6 pan-mTOR inhibitors (in comparison with rapamycin) and investigated effects of 6 pan-mTOR inhibitors on rapamycin-sensitive and -insensitive activities of mTOR, cell proliferation and geroconversion: Torin 1, Torin 2, AZD8055, PP242, KU-006379 and GSK1059615.

As predicted by theory of TOR-driven aging, rapamycin extends life span and prevents age-related diseases. Yet, rapamycin (and other rapalogs such as everolimus) does not inhibit all functions of mTOR. Inhibition of both rapamycin-sensitive and -insensitive functions of mTOR may be translated in superior anti-aging effects. However, potential benefits may be limited by undesirable effects such as inhibition of cell proliferation (cytostatic effect) and cell death (cytotoxic effect). In fact, pan-mTOR inhibitors have been developed to treat cancer, so they are cytostatic and cytotoxic at intended anti-cancer concentrations. Yet, the window between gerosupressive and cytotoxic effects exists. At optimal gerosuppressive concentrations, pan-mTOR inhibitors caused only mild cytostatic effect. For Torin 1 and PP242, the ratio of gerosuppressive (measured by RPP) to cytostatic concentrations was the most favorable. The ratio of anti-hypertrophic to cytostatic concentration was similar for all pan-mTOR inhibitors. Gerosuppressive effect of pan-mTOR inhibitors (as measured by RPP) was equal to that of rapamycin because it is mostly associated with inhibition of the S6K/S6 axis. Yet anti-hypertrophic effect as well as prevention of SA-beta-Gal staining and large cell morphology was more pronounced with pan-mTOR inhibitors than with rapamycin. Also, at optimal concentrations, all pan-mTOR inhibitors extended loss of re-proliferative potential in stationary cell culture more potently than rapamycin.

At gerosuppressive concentrations, pan-mTOR inhibitors should be tested as anti-aging drugs. Life-long administration of pan-mTOR inhibitors to mice will take several years. Yet, administration of pan-mTOR inhibitors can be started late in life, thus shortening the experiment. In fact, rapamycin is effective when started late in life in mice. Optimal doses and schedules of administration could be selected by administration of pan-mTOR inhibitors to prevent obesity in mice on high fat diet (HFD). It was shown that high doses of rapamycin prevented obesity in mice on HFD even when administrated intermittently. Testing anti-obesity effects of pan-mTOR inhibitors will allow investigators to determine their effective doses and schedules within several months. It would be important to test both rapamycin-like agents such as Torin 1 and rapamycin-unlike agent such as Torin 2 or AZD8085. Selected doses and schedules can then be used to extend life-span in both short-lived mice, normal and heterogeneous mice as well as mice on high fat diet. These experiments will address questions of theoretical and practical importance: (a) role of rapamycin-insensitive functions of mTOR in aging. We would learn more about aging and age-related diseases. (b) can pan-mTOR inhibitors extend life span beyond the limits achievable by rapamycin.

A Profile of Craig Venter and Human Longevity Inc.

Despite all the publicity, Human Longevity Inc. is a personalized medicine company rather than a longevity science company, intended to be the seed for a new industry that provides an incremental advance on present day customization of medicine through use of genetics. As I've said for a while now, this sort of application of genetics is not the path to significant enhancement of human longevity. All that this industry can do in the near term is inform us more accurately as to why the natural variations in human longevity exist, and provide ways to move someone from a slightly lower life expectancy bracket into a slightly higher life expectancy bracket. The latter is something that you can do for yourself today by undertaking exercise or calorie restriction. This is fiddling small change in the bigger picture. In that bigger picture, it is clear that we all age for the same underlying reasons: exactly the same forms of accumulated cell and tissue damage drive aging in all of us. Effective therapies to treat the causes of aging - and thereby produce radical life extension of decades at first and centuries later - will repair this damage, and will thus be exactly the same for everyone, with a massive scale of production to drive down the costs. The expensive undertaking of highly personalized medicine is simply not all that important when it comes to rejuvenation and the future of human longevity.

Craig Venter's latest venture, Human Longevity, Inc., or HLI, creates a realistic avatar of each of its customers - they call the first batch 'voyagers' - to provide an intimate, friendly interface for them to navigate the terabytes of medical information being gleaned about their genes, bodies and abilities. Venter wants HLI to create the world's most important database for interpreting the genetic code, so he can make healthcare more proactive, preventative and predictive. Such data marks the start of a decisive shift in medicine, from treatment to prevention. Venter believes we have entered the digital age of biology. And he is the first to embark on this ultimate journey of self-discovery. HLI has now submitted an analysis of its first 10,000 human genomes for publication, passing a milestone in creating what Venter hopes will be the world's largest, most comprehensive database of information to help transform healthcare and find answers to one of the oldest questions of all: is it possible to defy the ravages of ageing?

In 1998 Venter unveiled the privately funded Celera Genomics, which incurred the wrath of his peers in the public genome programme. He found himself battling with some of the world's biggest scientific institutions. The race propelled him onto front pages around the world when Celera unveiled its first human genome alongside the publicly funded version. Today, everybody in the field wants genomics to be part of medicine, he says. When it came to deciding where to bring about that merger, and finish the job that he started with Celera, Venter returned to the West Coast. On the coast, occupying land owned by the university, Venter has built the Californian campus of his not-for-profit J. Craig Venter Institute. He also set up Synthetic Genomics. This company is trying to understand the basic software of life and rewrite it to create novel organisms that can produce fuel, chemicals and medicines.

To synthesise the insights from these ventures, Venter founded HLI with stem cell pioneer Robert Hariri and technology entrepreneur Peter Diamandis, founder of the XPRIZE Foundation. Venter regards HLI as Celera on steroids. "The whole idea behind this is to identify the risk, then modify that risk so that you end up with longer periods of normal health. That is what the patient wants too. The patient does not want just more years but quality years." HLI started out stockpiling human genomes by sequencing them for partners that needed the data for research. This is only one ingredient of what Venter hopes will become the biggest genotype-phenotype database in the world. "Right now, we know less than 1 per cent of the genome in terms of how to really interpret it. Even with that, that's extremely valuable in being able to start this new preventative medicine paradigm where this information can help people understand their own health risk and hopefully save a lot of lives." So far, HLI has amassed the sequences of around 20,000 whole genomes, says Venter. But, of course, he wants even more. The company has room for more sequencing facilities on its third floor and is considering a second centre in Singapore, planning to rapidly scale to sequencing the genomes of 100,000 people per year - whether children, adults or centenarians, and including both those with disease and those who are healthy. By 2020, Venter aims to have sequenced a million genomes.

Venter wants to move from basic genetics to impacting individual lives "very directly. The most important part of that is nothing to do with the genome directly, but measuring phenotype and physiology and understanding their medical risk. That is what the microbiomes of its patients too - their cargo of gut microbes, which play a key role in health. Most valuable of all, Venter wants to link these various -omes to patients' phenotypes: their anatomy, physiology and behaviour. To do this, standard body measurements, online cognitive tests and blood samples are taken. The Health Nucleus adds yet more data using non-invasive tests. My tour begins with the room where HLI conducts a total body scan to create the avatars that inhabit its app. We pass through a succession of white rooms. There's one where visceral fat (which is linked to type 2 diabetes and cardiovascular disease) muscle volume, grey matter, white matter and more.

"We will be developing the evidence around this to make the case for preventive medicine." HLI has more work to do, such as organise a randomised controlled trial to compare the outcomes of people who get the tests with those who do not. Not everyone is convinced that HLI's testing will translate into improved health. Venter says that criticisms stem from the conservative nature of the medical community, notably when it comes to keeping the costs of screening under control. "That is the medical establishment saying: we want to keep doing what we do, we want to see people after they develop symptoms and have something wrong with them. The 'human longevity approach' is the exact opposite."


Fitness in Older Adults Correlates with Improved Brain Activity and Memory

Researchers here add more data to the known correlations between specific measures of fitness and cognitive function in later life. There are any number of potential mechanisms linked to exercise that might explain a slower age-related decline in memory and learning capacity in people who better maintain physical fitness, such as the state and activity of the immune system in the brain, as well as mitochondrial function, and vascular integrity. Pinning down specific contributions and the relative importance between mechanisms is, of course, a challenge.

Older adults who experience good cardiac fitness may be also keeping their brains in good shape as well. In what is believed to be the first study of its kind, older adults who scored high on cardiorespiratory fitness (CRF) tests performed better on memory tasks than those who had low CRF. Further, the more fit older adults were, the more active their brain was during learning. Healthy young (18-31 years) and older adults (55-74 years) with a wide range of fitness levels walked and jogged on a treadmill while researchers assessed their cardiorespiratory fitness by measuring the ratio of inhaled and exhaled oxygen and carbon dioxide. These participants also underwent MRI scans which collected images of their brain while they learned and remembered names that were associated with pictures of unfamiliar faces.

The researchers found that older adults, when compared to younger adults, had more difficulty learning and remembering the correct name that was associated with each face. Age differences in brain activation were observed during the learning of the face-name pairs, with older adults showing decreased brain activation in some regions and increased brain activation in others. However, the degree to which older adults demonstrated these age-related changes in memory performance and brain activity largely depended on their fitness level. In particular, high fitness older adults showed better memory performance and increased brain activity patterns compared to their low fitness peers. The increased brain activation in the high fitness older adults was observed in brain regions that show typical age-related decline, suggesting fitness may contribute to brain maintenance. Higher fitness older adults also had greater activation than young adults in some brain regions, suggesting that fitness may also serve a compensatory role in age-related memory and brain decline.


Will Senescent Cell Clearance Therapies Sink the Pensions and Annuities Industry?

The annuities and pensions industries, private and public, include some of the largest of all financial institutions. Collectively they are enormous, representing a staggering amount of money under management. To simplify a complex picture greatly, most of these programs take the form of a wager against longevity. The competing companies that issue annuities and manage pensions make offers of future payments to their customers based on the consensus predictions of life expectancy, and on their own private models that seek to improve on that consensus for specific demographics and thereby price the future more effectively than their competitors. Customers seek the greatest payout, while companies seek the payout that will maximize overall profit by some mix of attracting more customers from competitors and greater per customer profit. Customers that live longer than expected drain away profit, but historically this has been balanced by those who died early, as the consensus mortality predictions have on the whole been pretty good in the past.

Still, signing a contract is a long bet, realized over decades, and this is an era of very rapid progress in biotechnology, coupled with an important change in the focus of the medical research community, now looking at the causes of aging where before they did not. I have said for years that I think it likely that a majority of the presently outstanding wagers against longevity have now become very bad for the issuing companies. Why is this the case? Because it is plausible that the first rejuvenation therapies will be comparatively cheap, become quickly and widely available via medical tourism within a few years of their discovery, and prove effective. By "effective" I mean something in the ballpark of adding five years to the life expectancy of the average 60-year old. From where I stand, it looks like senescent cell clearance via senolytic drugs has the strong possibility of realizing this sort of outcome. Five years of additional payments for a large percentage of contracts would be a real issue for financial institutions: while an increasing amount of hedging has been voiced by actuaries over the past decade, the consensus models in the actuarial industry make no provision for a sudden jump in life expectancy along these lines. No company has priced in this possibility, as they'd be quickly outcompeted by their less wary competitors. Thus a large fraction of the contracts issued over the past 20-30 years, and of those issued today, are going to look increasingly risky as senescent cell clearance moves ahead.

Chaos in the financial industry as a result of all this is not a distant possibility, either. The solvency of financial institutions is a matter of perception as well as hard figures, but beyond this consider that annuities and pensions have been packaged and resold as derivatives, or otherwise used as collateral for leverage by the issuing organizations. Companies have borrowed on the value of their annuity and pension contracts, and high levels of leverage are very common these days, causing vulnerability to sudden changes in expectations. This is a failing of our era, as exhibited in numerous financial instruments over the past few decades; mortgages spring to mind, for example. The values of annuity and pension contracts packaged for the financial industry are assessed on an ongoing basis on an expectation of future income and expenses. As the consensus for future longevity shifts, companies will be greatly impacted or even bankrupted as a result of changes in predicted future outcomes, magnified by the leverage of assets.

To be clear, pensions are already heading towards a bad end in many countries even without the advent of effective rejuvenation therapies. Government bodies and other entities have found it all too easy to make unsustainable promises, or to let themselves be effectively looted by present caretakers. Insolvency and unsustainable future obligations are everywhere. This is one of many forms of widespread corruption in which those with the ability and the short-term interest steal from the public purse in the expectation that higher powers in government will bail them out. Historically, this doesn't seem like an unreasonable expectation, sad to say. So the losses will be spread out over the population, or kicked down the road for some future generation to be bankrupted by. Sooner or later there will be a major collapse in economic stability or currency or government in the affected regions - and the sooner the better, as the longer this goes on, the worse and more protracted the collapse that will result. Life will go on afterwards, the progression to the long-term golden future picking up where it left off, but all of this short-sightedness and self-sabotage in the near term is so very needless.

One of the ways in which the savaging of the annuities and pensions industry might be minimized is through a bailout of some sort. This is, as I said, quite a likely outcome given recent history, but all it does is make the larger economic problem worse. Further, it will probably happen again as new rejuvenation therapies emerge. Another possibility is for this industry to lobby for dissolution or alteration of existing contracts, which again seems like a plausible outcome, essentially the use of political power to carry out a form of fraud by force upon every counterparty who signed something that later proved inconvenient. It is also possible that the availability of senolytic therapies via medical tourism, and at a reasonably low cost, will not lead to widespread adoption rapidly enough to bankrupt annuity and pension companies. This seems to me unlikely to help make the problem very much smaller, however. This scenario would make the problem occur later, further down the line, say a decade after it might have happened with rapid adoption of therapies. If an increase of five years of life extension is bankrupting in 2020, it is likely to still be highly problematic in 2030: the majority of the problem contracts be will still be around, active, and their owners expecting to be paid for a long time yet.

Do I think it is worth putting money into an annuity? I think this is a good wager in a world in which issuing companies have infinite resources, but this isn't that world. Sooner or later you will get cut off, via one of the mechanisms mentioned above. The important risk is that this might happen sooner to the point at which you'd have been better off investing elsewhere. The whole situation is very uncertain on timing and outcomes over the next few decades, and that is rather the point I'm trying to make here.

Quantifying the Anti-Inflammatory Effects of Exercise

Researchers here quantify the degree to which exercise has immediate anti-inflammatory effects. This is one of the many ways in which exercise is beneficial for health. Rising chronic inflammation is characteristic of aging and the failing immune system, and contributes meaningfully to the progression of all of the common age-related diseases. Less inflammation is a good thing when considering long-term health.

It's well known that regular physical activity has health benefits, including weight control, strengthening the heart, bones and muscles and reducing the risk of certain diseases. Recently, researchers found how just one session of moderate exercise can also act as an anti-inflammatory. The findings have encouraging implications for chronic diseases like arthritis and for more pervasive conditions, such as obesity. The study found one 20-minute session of moderate exercise can stimulate the immune system, producing an anti-inflammatory cellular response. "Each time we exercise, we are truly doing something good for our body on many levels, including at the immune cell level. The anti-inflammatory benefits of exercise have been known to researchers, but finding out how that process happens is the key to safely maximizing those benefits."

The brain and sympathetic nervous system - a pathway that serves to accelerate heart rate and raise blood pressure, among other things - are activated during exercise to enable the body to carry out work. Hormones, such as epinephrine and norepinephrine, are released into the blood stream and trigger adrenergic receptors, which immune cells possess. This activation process during exercise produces immunological responses, which include the production of many cytokines, or proteins, one of which is TNF - a key regulator of local and systemic inflammation that also helps boost immune responses. "Our study found one session of about 20 minutes of moderate treadmill exercise resulted in a five percent decrease in the number of stimulated immune cells producing TNF. Knowing what sets regulatory mechanisms of inflammatory proteins in motion may contribute to developing new therapies for the overwhelming number of individuals with chronic inflammatory conditions."


Hostility Towards Paid Trials Searching for Significant Effects

This popular science piece is characteristic of a prevalent and hostile view of the growing practice of patient-funded clinical trials. In this model the patient pays a sizable portion of the costs, which certainly makes it a lot easier to gather larger amounts of data, as the trial organizers don't have to seek the funding themselves. On the other hand, it tends to rule out the ability to carry out a blind trial in which not everyone actually gets the treatment, as well as other similar refinements. That is a problem if the goal is to search for and quantify marginal effects, but if the point is to discover or rule out large effects, I'd argue that control groups are not necessary. The control in that case is the established progression for patients who do not get the treatment, or who undergo existing, marginal treatments. We are at the stage in the development of medicine to treat aging in which marginal effects, such as those resulting from the use of metformin as a calorie restriction mimetic, should be discarded as uninteresting. Once at the stage of trying things in human studies, the research community should be filtering for significant effects, such as those obtained by clearance of senescent cells. Given the poor state of funding for aging research in general, methods that can pull in more resources to obtain more data should be applauded.

In the case of the approach being trialed here by Ambrosia, as mentioned earlier this year I think our expectations should be low, and the outcome I expect is for there to be no significant benefit. The only ethical question worthy of consideration is whether those involved then do the right thing: publish the data, shut up shop, and move on to the next project. Transfusions of young blood to old individuals are not producing benefits in mice, and there is reason to think that the beneficial outcomes observed in old mice due to parabiosis, the linking of circulatory systems between an old and a young individual, are due to factors or circumstances not replicated by periodic transfusion. It isn't difficult to imagine that beneficial outcomes require the youthful system reacting in a dynamic way to the presence of aged signals, for example, or - as suggested by some researchers recently - that it is nothing more than a consistently maintained dilution of problem signals in the aged environment.

Just off a winding highway along the Pacific coast in Monterey, California, is a private clinic where people can pay $8,000 to have their veins pumped with blood plasma from teenagers and young adults. Jesse Karmazin is the entrepreneur who made the practice possible, by launching a clinical trial on the potential of "young blood" through his startup Ambrosia. He says that within a month, most participants "see improvements" from the one-time infusion of a two-liter bagful of plasma, which is blood with the blood cells removed. Several scientists and clinicians say Karmazin's trial is so poorly designed it cannot hope to provide evidence about the effects of the transfusions. And some say the pay-to-participate study, with the potential to collect up to $4.8 million from as many as 600 participants, amounts to a scam. Ambrosia says it will enroll almost anyone over 35, and the fees of $8,000 per person could add up. But Karmazin rejects the idea he is out to generate profits. He says that money is needed to cover the cost of clinical procedures, laboratory tests, and the plasma.

What's certain is that it's based on some intriguing if inconclusive science. Karmazin says he was inspired by studies on mice that researchers had sewn together, with their veins conjoined, in a procedure called parabiosis. Over the last decade or so, such studies have offered provocative clues that certain hallmarks of aging can be reversed or accelerated when old mice get blood from young ones. Yet these studies have come to conflicting conclusions. Further, parabiosis experiments offer little insight into how Ambrosia's one-time transfusions will affect people. Despite such uncertainties, the potential of young blood to treat disease is being explored in a number of clinical trials.

In 2014, Stanford University neuroscientist Tony Wyss-Coray demonstrated that old mice had increased neuron growth and improved memory after about 10 infusions of blood from young mice. That prompted Wyss-Coray to launch a small company, Alkahest to test transfusions of plasma from young people in the treatment of Alzheimer's disease. Alkahest's clinical study is more conventional than Ambrosia's: it does not charge participants, it expects to enroll only 18 volunteers, and it is initially looking at how well the elderly can tolerate small doses of plasma. Like several other researchers and bioethicists, Wyss-Coray worries about the fact that Ambrosia's trial is funded by participants rather than investors. "People want to believe that young blood restores youth, even though we don't have evidence that it works in humans and we don't understand the mechanism of how mice look younger."

The formal goal of the Ambrosia study is to measure the effect of young plasma on about 100 biomarkers. Before the infusion, and one month after, all participants have their blood analyzed for biomarkers. But Irina Conboy, a professor at the University of California, Berkeley, thinks the biomarker results will be meaningless: for one thing, the study lacks a control arm with patients who don't get plasma. Blood biomarkers, she says, change for many reasons. She's also wary of Alkhest's study on Alzheimer's patients. Last year, she and colleagues found that older mice whose blood was partially replaced with younger blood saw few benefits. "Both studies are hurt by the same problem, and the problem is that there is no evidence to suggest that an infusion of plasma from young to old animals reverses aging."


A Sizable Portion of the Damage of Chemotherapy may be due to Cellular Senescence

Now that much more attention and funding is turning to cellular senescence as a cause of aging, a fair number of new discoveries are being made regarding the specific links between age-related disease and the growing presence of senescent cells in old tissues. Some of them seem almost obvious in hindsight, connections that researchers should have long assumed to be likely, such as senescent foam cells accelerating the progression of atherosclerosis. Now that senescent cells can be cleared effectively in the laboratory, proof of these connections is comparatively simple to obtain, and so the evidence is piling up month after month. The open access paper I'll point out today provides evidence for another connection that has the look of something that should be self-evident in hindsight, between cellular senescence and the harmful side-effects of cancer chemotherapy. It is PDF only at the time of writing, I'm afraid.

Chemotherapy at the levels needed to suppress cancer is enormously unpleasant, sometimes even fatal, and no-one with any other option would ever undergo such a treatment. Worse, it has a large impact on future life expectancy, as the outcomes for cancer survivors having undergone chemotherapy look much the same as those of life-long smokers. But why is chemotherapy so harmful? We can point to numerous side-effects ranging from outright toxicity to dysregulation of important cellular activities in a number of organs. The one thing that all chemotherapies should achieve along the way is to create a lot of senescent cells, however. Cellular senescence is a defense against toxic environments and cellular damage, and in modest amounts it lowers the risk of cancer by shutting down replication in those cells most at risk. Beyond producing senescence in bystander cells by putting them under stress, chemotherapy should also make a lot of cancerous cells senescent. For many chemotherapy drugs that is the intended goal. As is always the case for senescent cells, many will be destroyed by the immune system or their own self-destruct programs, but a fraction will linger. Chemotherapy might be thought of as the equivalent of decades of normal creation and destruction of senescent cells, run through on fast forward.

The harm caused by senescent cells is a matter of signaling. They secrete a mix of molecules, the senescence-associated secretory phenotype (SASP), that spurs chronic inflammation, damages the surrounding extracellular matrix, changes the behavior of normal cells for the worse, and more. If 1% of the cells in a tissue are senescent, that is sufficient to cause measurable dysfunction and decline in most organs. Given this, it seems very logical that to the degree chemotherapy pushes cells into a senescent state, it will harm patients in the long term via these mechanisms. This is an opportunity as well as a realization, however: in the years in which chemotherapy is on the way out, to be replaced by immunotherapy and other approaches, it might be made less damaging to patients through the use of therapies to clear out the senescent cells created during cancer treatments.

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse

Cellular senescence is a complex stress response whereby cells irreversibly lose the capacity to proliferate, accompanied by numerous changes in gene expression. Many potentially oncogenic insults induce a senescence response, which is now recognized as a potent tumor suppressive mechanism. Other senescence-inducing stimuli include radiation, genotoxic drugs, tissue injury and remodeling, and metabolic perturbations. Moreover, senescent cells accumulate with age in several vertebrate organisms, and their elimination can delay the onset of several age-associated disorders in mice. Senescent cells most likely promote aging through the senescence-associated secretory phenotype (SASP): the increased expression and secretion of inflammatory cytokines, chemokines, growth factors and proteases.

Genotoxic and cytotoxic drugs are widely used as anti-cancer therapies. Most such agents target proliferating cells through distinct, cell cycle-dependent mechanisms. Their cytotoxicity for many types of dividing cells often leads to side effects, which include immunosuppression, fatigue, anemia, nausea, diarrhea and alopecia. Moreover, clinical studies of cancer survivors treated during childhood suggest that some chemotherapies causes a range of long-term side effects that resemble pathologies associated with aging, including organ dysfunction, cognitive impairment and secondary neoplasms. Many chemotherapeutic drugs alter cellular states, including the induction of senescence, in cancer cells and the tumor microenvironment. Therapy-induced senescence (TIS) can stimulate immunosurveillance to eliminate tumor cells, but can also be a source of chronic inflammation and drug resistance. Indeed, a recent study showed that treatment of breast cancer patients with anthracycline and alkylating agents durably induces cellular senescence and a SASP in a p16INK4a-dependent, telomere-independent fashion. Expression of the tumor suppressor p16INK4a increases with age and is a robust senescence marker in numerous mouse and human tissues.

To more precisely assess the physiological effects of TIS in vivo, we used a recently described mouse model (p16-3MR) in which p16INK4a-positive senescent cells can be detected in living animals, isolated from tissues, and eliminated upon treatment with an otherwise benign drug. Using this approach, we determined the contribution of senescent cells to a variety of common short and long-term chemotherapy toxicities. Additionally, we used a senescence marker to assess the relationship between senescent cells and chemotherapy toxicity in human patients. We show that TIS cells contribute to local and systemic inflammation, as determined by increased expression of pro-inflammatory SASP factors in tissue and increased levels of inflammatory cytokines in sera, which is reduced after removal of senescent cells in vivo using p16-3MR transgenic mice. Further, the elimination of senescent cells limited or prevented the development of multiple adverse reactions to chemotherapy.

In addition, weeks after chemotherapy treatment, TIS cells were important for bone marrow suppression and development of cardiac dysfunction, both limiting factors for the use of some chemotherapeutic agents, particularly the anthracyclines. The promotion of cardiac dysfunction might be due to either cardiac senescent cells, which we show are primarily endothelial cells, or senescence-induced inflammation. Senescent non-tumor cells were important for cancer relapse and spread to distal tissues after chemotherapy, at least in the breast cancer model we used. Moreover, clearing senescent cells increased overall spontaneous physical activity in the presence or absence of cancer. Importantly, these murine findings were validated in a human cohort, showing that p16INK4a expression in peripheral T-cells predicts chemotherapy-induced fatigue in human patients with breast cancer. We believe this latter finding is consistent with recent work showing that aging is the major risk factor for long term (more than 2 or more than 5 years) fatigue after chemotherapy treatment.

The data presented here show a direct role for TIS cells in mice, and a strong correlation between fatigue and senescent cells in humans. An alternative approach, then, is to develop therapies that can selectively target senescent cells (senolytics) and/or the SASP, an approach that recently showed promise. Indeed, the administration of a senolytic agent, ABT-263, efficiently eliminated senescent cells, improved physical activity, and reduced cancer relapse in mice treated with Doxorubicin. Such therapeutic approaches will, of course, need to carefully consider whether there are beneficial effects of TIS, such as promoting the repair of tissues damaged by the chemotherapy or the potential of senescent cells to activate the immune response to tumor cells. Nonetheless, the pharmacological removal of senescent cells from the tumor microenvironment might be an innovative strategy to limit toxicities of current chemotherapies with consequent improvements in the health span and possibly life span of cancer patients.

The Fifty Year Anniversary of the First Cryopreservation

Fifty years ago, the first human was cryopreserved in the hopes of future revival. To this day, cryopreservation remains the only chance at a longer life in the future for all those who will age to death prior to the advent of effective rejuvenation therapies. James Bedford's preservation was a straight freezing with all the attendant tissue damage, unlike the vitrification techniques used today. It is certainly the case that future restoration would require exceptionally comprehensive control and manipulation of molecular biology, of the sort enabled by a mature molecular nanotechnology industry. The degree to which the data of his mind still exists despite ice crystal and fracture damage, or can be reconstructed, is an open question left to be answered by future generations.

Cryonics has long been expected to be a last in first out endeavor should it succeed: those preserved more recently, and thus with better preservation techniques, will be the easiest to revive - though of course "easiest" is a relative measure here. All of cryonics is in effect a wager on a decent preservation process, survival of the preservation organization, and then a golden future of advanced technology and great wealth. That is nonetheless a wager that looks very favorable in comparison to the alternative options at the end of life.

Bedford was preserved a few years prior to the establishment of professional cryonics organizations, and in that early stage of the industry some of those organizations were poorly run. Preserved individuals were lost to thawing. Of all the initial patients from the late 1960s and early 1970s, only Bedford remains. Depending on where you wish to draw the line between life and death, he might be counted as the world's oldest surviving human. For so long as the data of the mind remains, encoded in the fine structures of brain tissue, there is the possibility of future restoration in an age of far greater and more capable technology.

Dr. James Hiram Bedford, a former University of California-Berkeley psychology professor died of renal cancer on Jan. 12, 1967. Bedford was the first human to be cryonically preserved - that is, frozen and stored indefinitely in the hopes that technology to revive him will one day exist. He's been at Alcor since 1991. His was the first of 300 bodies and brains currently preserved in the world's three known commercial cryonics facilities: Alcor; the Cryonics Institute in Clinton Township, Michigan; and KrioRus near Moscow. Another 3,000 people still living have arranged to join them upon death.

Cryonics patients are no longer frozen, but "vitrified." First, the body is placed in an ice-water bath. Then, ice-resistant chemicals are pumped into the body, taking the place of water in the blood. That way, in the next step, when the body or brain is cooled to well-below freezing using nitrogen gas, it hardens without forming cell-damaging ice. Vitrification has been used to effectively preserve blood, stem cells, and semen. But restoring life to a vitrified human - or to an organ as complex as the brain - remains an unfathomably distant prospect. If there is a divide on cryonics in the scientific community, it's between neuroscientists willing to state that reanimation is at least within the realm of physical possibility, and those who believe it's so unlikely that selling even the hope is unethical.

Bedford's preservation in the pre-vitrification days was a crude, ad hoc affair. He legally died in a southern California nursing home at the age of 73, after donating his body to the Life Extension Society, a group of early cryonics enthusiasts. Hours after death he was injected with the solvent dimethyl sulfoxide in an attempt to stave off tissue damage, packed in a Styrofoam box of dry ice, and eventually submerged in liquid nitrogen. For the next 27 years, Bedford's liquid-nitrogen-filled chamber was constantly on the move, as various cryonics companies folded or were forced to move for insurance or regulatory problems. The $100,000 he'd set aside to pay for his body's long-term care evaporated as his wife and son faced legal challenges from other family members objecting to his unconventional resting place. From 1977 to 1982, frustrated with the high cost of maintenance, they appear to have kept his unit in a self-storage facility in southern California, occasionally topping off the liquid nitrogen themselves. Upon his wife's death in 1982, Bedford's body and container were entrusted to the company that became Alcor. Then-director Jerry Leaf, who died and was cryopreserved in 1991, took out a life insurance policy on himself to fund Bedford's ongoing care.


Telomere Length and Good Health Practices

One of the original researchers involved in telomere length studies is currently publishing a book on general health. It is in no way novel in the lineage of such things save for the relentless emphasis on telomeres, the repeating DNA sequences that cap the ends of chromosomes. Telomeres shorten with each cell division, and stem cells generate daughter cells with fresh, long telomeres, so the average length in a cell type is some function of cell division rates and stem cell activity. The thing is, telomere length as presently measured in immune cells from a blood sample is actually a terrible biomarker (of aging or health status) for individual purposes: the well-publicized erosion of average telomere length with age is a statistical phenomenon that only shows up in the data for large populations, and even there it isn't a robust measure. Pick one individual and their health concerns and it isn't yet at all clear that telomere length measures have any practical utility. Two people with the same condition can have quite different telomere lengths, and changes over time are not yet correlated well with health status for any one individual. This is far worse for use in diagnostic medicine than the sort of long-standing metrics obtained from standardized blood tests at the present time.

Molecular biologist Elizabeth Blackburn shared a Nobel Prize for her research on telomeres - structures at the tips of chromosomes that play a key role in cellular aging. But she was frustrated that important health implications of her work weren't reaching beyond academia. So along with psychologist Elissa Epel, she has published her findings in a new book aimed at a general audience - laying out a scientific case that may give readers motivation to keep their new year's resolutions to not smoke, eat well, sleep enough, exercise regularly, and cut down on stress. The main message of "The Telomere Effect," is that you have more control over your own aging than you may imagine. You can actually lengthen your telomeres - and perhaps your life - by following sound health advice, the authors argue, based on a review of thousands of studies.

Telomeres sit at the end of strands of DNA, like the protective caps on shoelaces. Stress from a rough lifestyle will shorten those caps, making it more likely that cells will stop dividing and essentially die. Too many of these senescent cells accelerates human aging. This doesn't cause any particular disease, but research suggests that it hastens the time when whatever your genes have in store will occur - so if you're vulnerable to heart disease, you're more likely to get it younger if your telomeres are shorter. Other researchers in the field praised Blackburn and Epel's efforts to make telomere research relevant to the general public, though several warned that it risked oversimplifying the science. "I think it's a very difficult thing to prove conclusively" that lifestyle can affect telomere length and therefore lifespan, said Harvard geneticist and anti-aging researcher David Sinclair. "To get cause-effect in humans is impossible, so it's based on associations." Judith Campisi, an expert on cellular aging at the Buck Institute for Research on Aging in Novato, Calif., said the underlying research is solid. "If you have a terrible diet and you smoke, you're definitely shortening your life, and shortening your telomeres. Short telomeres increase the likelihood of cells becoming senescent and producing molecules that lead to inflammation, which is a huge risk factor for every age-related disease. So there is a link there, it's just not this exclusive magic bullet, that's all."

One of the challenges with telomere research is that most studies measure the length of telomeres in blood cells. But it may be that the liver is aging faster or slower than the blood - we're not all one age throughout. By measuring telomere length in the blood, "what you're really reporting on is the capacity of immune stem cells to function well," said Matt Kaeberlein, who studies the molecular basis of aging at the University of Washington. "What this may be really telling us is the immune system may be particularly sensitive to lifestyle and environmental factors." Kaeberlein said he's only at the periphery of telomere research, but is skeptical about the predictive value of shorter versus longer telomeres. "It's not at all clear whether the methods are quantitative enough or of high enough resolution to really make those kinds of arguments. I think it has the potential to be a biomarker predicting health outcomes, but I don't know that I would feel comfortable saying people should make lifestyle changes based on a measure of their telomere length."


Why Rejuvenation Research Startups Go Quiet Following Launch

There are a number of young startup biotechnology companies presently working on the basis for rejuvenation therapies. Many of the interesting ones are focused on senescent cell clearance, the class of therapy that is arguably closest to the clinic. Some of those, like Oisin Biotechnologies, are supported by our community: seed funding from non-profits like the Methuselah Foundation and SENS Research Foundation, and angel funding from some of the same folk as put up matching funds for the yearly SENS rejuvenation research fundraisers. Typically, however, after the initial declaration of intent these companies go silent. Unless you're an insider, the next thing you'll hear will be some way down the line, a declaration of either success or failure following the initial few years of research and development. Why is this the case? Don't companies want greater public exposure? If you've ever been involved in a small startup, the silence won't be all that surprising. But since most of us haven't, it might seem a little inexplicable. What is going on here?

There are two reasons as to why this silence is the usual state of affairs for the first few years of most startup companies. The first reason is that talking to the outside world is a low priority task for most classes of company in their earliest stages. The big risk is not that no-one will know that you're striving to prove a thesis in business or research, but rather that you'll simply fail, or fail to achieve the goal within the runway provided by current funding. Unless publicity is a prerequisite to avoid near-future failure, and for most companies it isn't, then it will tend to drop off the bottom of the to-do list. That work vanishes along with every other non-essential task, and usually quite a few tasks that would be considered essential in a more sedate environment. The typical state of action in any early stage startup is that there is far too much to accomplish, too few people to accomplish it with, and the clock is ticking loudly on the way to seemingly impossible deadlines. This is just the way of things. No matter how carefully you scope the work at the outset, it always multiplies. Successful teams narrow the focus considerably and quickly jettison nonessential work. For biotechnology companies, "nonessential" covers pretty much everything except the actual labwork and the financial and legal work needed to run a company and raise funding.

The second and more important reason for silence relates to the government regulation of fundraising. If you've ever worked inside an early stage startup, then you'll have noticed that when raising capital, half of the founders and executives essentially vanish for months. Raising venture funding is a full time job, one added to the other full time job of actually running the startup. It is the regulatory rules, and not the workload, that keeps the company quiet, however. In the US, the Securities and Exchange Commission (SEC) rules regarding venture investment are baroque, and there is a layer of convention and precedent atop the regulation as written that guides companies to only a few of the many possible options for organizing the process, but the bottom line is that selling part of an early stage company to investors via an open, public solicitation is very hard to achieve in a cost-effective manner. The disadvantages in terms of time, risk, and transaction costs far outweigh any possible advantage. Thus founders opt for private fundraising efforts, working through their personal connections to reach potential investors.

It isn't hard to see the regulatory capture at work in this situation; the existing regulations on public versus private fundraising are a large part of why the venture community exists in its present highly networked and nepotistic form. Unfortunately, any sort of public disclosure of progress during the fundraising process might be considered solicitation by the SEC, resulting in possible censure or legal action against a company and its founders - and so companies go quiet when fundraising. This is starting to change a little with the new crowdfunding rules introduced this year, but they bring their own significant disadvantages, not least of which being a lack of convention to guide expectations regarding what SEC bureaucrats will and will not consider actionable violations. The SEC is the epitome of selective, capricious enforcement of unclear rules, which is why convention and precedent have become so important, and why founders err on the side of caution when it comes to public communications.

The idealized view of a successful startup is that it kicks off with a little seed funding from the founders, using those resources to obtain evidence for the initial thesis in some way. Then on the basis of that evidence, assuming success, the next stage is to obtain further funding, raised in a friends and family round. That funding is used to improve the evidence to the point at which institutional investors would be willing to join in - and hopefully by that point, the evidence is something along the lines of revenue from actual customers, or a working prototype therapy proved in mice, or similar. Then the company opens what is known as a series A round, solicits professional investors, raises much more money than was obtained from founders, friends, and family, hires staff, slows the pace a little, and starts to look more like a regular company thereafter as it moves towards profitability. Following series A there is typically more public communication and a lengthy gap before any further funding rounds. This is the idealized view, however. In reality, there might be any number of discrete or opportunistic fundraising events prior to series A. Over this span of time, the company founders are typically making a range of new connections in their industry and in the venture and angel community, and any sort of recent publicity for the company would constrain the ability to turn those connections into funds that can be usefully applied to ensuring the company succeeds.

So, frustrating as it might be, public silence is the way of things for early stage companies for the foreseeable future.

Glial Cell Gene Expression Changes as a Potential Biomarker of Aging

The development of robust and reliable biomarkers that reflect biological age is a necessary step for the future development of rejuvenation therapies. The existence of such biomarkers will make it much less expensive and time-consuming to assess the effectiveness of potential new therapies at all stages of the research and development pipeline, which in turn will lead to more rapid progress in this field. Here, researchers assess changes in gene expression in neurons and their supporting cells in brain tissue, and find that the changes in glial cells are those that best correlate with age:

The relationship between aging and neurodegeneration raises the possibility of shared transcriptional and post-transcriptional gene regulation programs; however, we still lack a comprehensive transcriptome-wide picture of the effects of aging across different human brain regions and cell types. Apart from the study of region-dependent microglial response to aging, the importance of both region- and cell-type-specific changes in the aging brain remains poorly understood. Studies have been hampered by the limited availability of cross-regional post-mortem tissue across a range of ages. To overcome these limitations, we analyzed gene expression patterns in ten brain regions (including cortical and sub-cortical areas) using more than 1,800 brain samples from two large independent cohorts, representing the most comprehensive human aging brain gene expression analysis to date. We report striking changes in cell-type-specific expression patterns across different brain regions, which revealed major shifts in glial regional identity upon aging in the human brain.

By current consensus, astrocyte (AC) and neuronal numbers appear generally preserved in aging. It is clear, however, that Alzheimer's disease (AD) and other neurodegenerative diseases for which age is a major risk factor are associated with inflammatory changes mediated by microglia (MG). Our findings show that cell-type-specific genes delineate samples based on both age group and brain region. Aging was the major determinant of glia-specific gene expression shifts in regional identity, while such changes were not evident in neuron-specific genes. Genes specific for neurons and oligodendrocytes (OLGs) generally decreased their expression upon aging, while MG-specific genes increased their expression profiles, consistent with the known MG activation in aging. A trend toward increased expression of MG-specific genes was observed in all regions upon aging, with corresponding upregulation of genes with immune or inflammatory functions.

In addition to glial changes, we also observed a decreased number of neurons with large cell bodies, which represent approximately 20% of neurons in the cortex. Although we did not attempt to directly identify the neuronal subtypes in the present study, neurons with the largest cell bodies are likely to be associative pyramidal neurons. Furthermore, these neurons were previously indicated to be most vulnerable to aging. While our analysis indicates that the decrease in these pyramidal neurons may be the primary source of the downregulation of neuron-specific genes, our findings regarding the cortical neuronal cells remain speculative due to the limited number of individuals used for the imaging analyses.

Age is the major risk factor for both Alzheimer's disease (AD) and Parkinson's disease (PD), the two most prevalent neurodegenerative diseases. It is becoming clear that the pre-clinical stage of AD begins decades before clinical manifestation. This pre-clinical stage has been termed "the cellular phase," because it involves changes in interactions among all cell types in the brain, with the most dramatic changes taking place in AC, MG, and vasculature. We find a corrosion of glial region-specific gene expression in aging, with the genes specific for AC, MG, and endothelial cells being the best predictors of age. By simultaneously assessing changes in cell-type-specific genes across multiple brain areas, our study takes a step toward providing a comprehensive framework of the molecular and cellular changes in human aging. While our primary aim was to deconvolute the cell-type-specific signatures present within large databases of age-related transcriptional changes, we also made a step toward interpreting these in light of changes in counts of OLGs and neuronal cells. Integration of further genome-wide and single-cell data from human tissues samples and cell and animal models will be required to fully understand the cellular and molecular mechanisms underlying the observations in our study. Altogether, our study indicates that the cellular changes during aging involve a dramatic shift in the regional identity of glia, and it provides a resource for further studies of the relationship between aging and the cellular phase of dementia.


Transplant of Engineered Retinal Tissue Restores Light Sensitivity in Blind Mice

One of the challenges inherent in testing potential methods of restoring lost retinal function is that mice cannot readily explain the degree to which their sight is restored. So the researchers here can demonstrate restored light sensitivity and neural integration of transplanted retinal tissue, but they cannot say how the procedure will affect quality of vision without going on to trial the technique in human subjects.

Retinal degeneration is mostly a hereditary disease that is characterized by the death of photoreceptors - the light-sensitive neurons in the eye - which eventually leads to blindness. While many have attempted to treat the disease through retinal transplants, and some have shown that transplanting graft photoreceptors to the host without substantial integration can rescue retinal function, until now, no one has conclusively succeeded in transplanting photoreceptors that functionally connect to host cells and send visual signals to the host retina and brain. The researchers studied this problem using a mouse model for end-stage retinal degeneration in which the outer nuclear layer of the retina is completely missing. This is an important issue because in clinical practice this type of therapy would most likely target end-stage retinas in which of the photoreceptors are dead and the next neurons up the chain do not have any input.

Researchers have recently shown that 3D retinal sheets derived from mouse embryonic stem cells develop normal structure connectivity. "Using this method was a key point. Transplanting retinal tissue instead of simply using photoreceptor cells allowed the development of more mature, organized morphology, which likely led to better responses to light." In order to assess the success of the transplantations, the team integrated some modifications to the retinal sheets and the model mice. They used a fluorescent protein to label the ends of the photoreceptors, which is where they would connect to the host neurons - the bipolar retinal cells - and ultimately the brain. After labeling the host retinal bipolar cells with a different fluorescent protein, they found that the labeled cell terminals from the graft did indeed make contact with the cells labeled in the host, indicating that the newly grown photoreceptors naturally connected themselves to the bipolar cells in the model mice.

To assess whether the mice could see light, the researchers used a behavioral learning task. Mice with normal vision can learn to associate sounds or light with different events. While the model mice who lacked a photoreceptor layer in their retinas could not learn to associate anything with light before surgery, they could after the transplant, provided that a substantial amount of the transplant was located in the correct place. This means that not only did the new cells in the retina respond to light, but the information traveled to the brain and could be used normally to learn. "These results are a proof of concept for using induced pluripotent stem cell (iPSC)-derived retinal tissue to treat retinal degeneration. We are planning to proceed to clinical trials in humans after a few more necessary studies using human iPSC-derived retinal tissue in animals. Clinical trials are the only way to determine how many new connections are needed for a person to be able to 'see' again."


Amyloid and Tau have Synergistic Effects on the Progression of Alzheimer's Disease

Alzheimer's disease is both an amyloidosis and a tauopathy. The dysfunction and death of neurons is driven by rising levels of amyloid-β and altered forms of tau, both of which form solid deposits in brain tissue. The accumulation of misfolded proteins and metabolic waste in this way is characteristic of aged tissues and happens to everyone, but in Alzheimer's patients the process is far more pronounced, the solid aggregates far more abundant. The relationship between these aggregates and the death of neurons is very complex, and at some levels the details still much debated, involving a cascade of intermediary interactions and proteins. There is plenty of room for new theory and new discoveries. In an open access paper I noticed recently, and linked below, researchers provide evidence for the progression of Alzheimer's to be more than just an additive consequence of amyloid and, separately, tau. The two forms of aggregrate and the consequences of their presence interact with one another to make the outcome worse than that.

This should probably not be all that surprising. All of our biological systems interact with one another, directly and indirectly, and at all scales, whether considering nanoscale processes inside a single cell or macroscopic process linking the behaviors of organs. Consider the effects of changing blood pressure and the number of different organs impacted, for example. When it comes to the forms of cell and tissue damage that cause aging, these too interact with one another. To pick one example, the declining effectiveness of the immune system accelerates the contribution of cellular senescence to aging, allowing ever more of these unwanted cells to linger rather than be destroyed. In turn senescent cells create greater levels of chronic inflammation, making the immune system more dysfunctional than it would otherwise be. Similar interactions are either known or there to be found between other classes of damage: mitochondrial DNA deletions; cross-linking in the extracellular matrix; and so forth. This synergy between forms of damage, creating a downward spiral of accelerating malfunction and breakage, is prevalent in all complex systems, not just in our biology.

What does all this mean for ongoing work on producing a viable therapy for Alzheimer's disease? It is already clear that both amyloid-β and tau aggregates should be cleared, with amyloid clearance somewhat ahead of tau clearance at the present time. The dominant strategy of immunotherapy has proven to be a far greater challenge to implement than desired, with the first tangible, promising results in human trails only recently achieved. One thing to consider is that, depending on the degree of synergy, the first successful therapy for amyloid-β clearance may be more effective than hoped, even though it leaves all of the tau in place. It may also mean that a combination of poor therapies that only partially impact both amyloid-β and tau might be worth trying, even though each on its own isn't effective enough to move beyond trials. That said, one of the other major challenges in treat Alzheimer's is that more than half of the patients suffer from other forms of dementia as well, commonly vascular dementia, and that distinct pathology may well mask many of the benefits produced by clearance of amyloid or tau. Repairing the later stages of neurodegeneration is a challenging business, all things considered.

Synergistic interaction between amyloid and tau predicts the progression to dementia

Alzheimer disease (AD) is characterized by the progressive accumulation of extracellular amyloid-β (Aβ) plaques, intracellular inclusions of hyperphosphorylated tau in tangles, and neuronal degeneration. The most widely accepted model of AD progression proposes a cascade of neuropathological events in which abnormal levels of Aβ, neurofibrillary tangles, and neurodegeneration precede dementia. The idea of pathophysiological progression was incorporated by the criterion for predementia phase of AD, which recognizes that the coexistence of abnormal Aβ and neurodegeneration biomarkers better identify mild cognitive impairment (MCI) patients who will progress to dementia. This notion has been supported by recent observations demonstrating that MCI Aβ+ individuals with neurodegenerative changes have higher rates of neuropsychological decline as compared with MCI biomarker negative participants. Yet a key question that remains unanswered is whether the highest rate of progression to dementia in MCI Aβ+ individuals with downstream cascade abnormalities is due to a synergistic effect between the coexistent brain pathologies or simply the sum of their deleterious effects.

Given the emphasis of the current literature on the combination of Aβ and neuronal degeneration biomarkers, the clinical fate of MCI patients with abnormal Aβ plus p-tau proteins is scarcely known. The importance of characterizing the synergistic effect between Aβ and p-tau on the development of dementia goes beyond the understanding of the mechanisms of disease progression. Determination of such synergism has immediate implications for the population enrichment of clinical trials testing anti-amyloid or anti-tau therapy. For example, if Aβ and p-tau synergistically determine dementia, the enrichment of clinical trial populations with carriers of both pathologies would increase the rate of clinical progression without loss of therapeutic effectiveness. Conversely, if Aβ and p-tau simply add their deleterious effects on cognitive decline, carriers of both pathologies would lead to a reduced therapeutic effectiveness of an intervention targeting only one of these proteinopathies, given the residual effect of the untreated protein on the clinical course of the disease.

Although several studies have shown that Aβ and p-tau independently predict disease progression, a hypothetical framework proposes that both proteinopathies synergistically potentiate downstream neurodegeneration. The presence of such a synergism would suggest that the effect of Aβ and p-tau on the progression of AD taken together is greater than the sum of their separate effects at the same level. In fact, recent findings from our laboratory support this framework showing that the synergistic effect between brain Aβ and p-tau rather than neurodegeneration drives AD-related metabolic decline in a cognitively normal population. Similarly, in vivo studies conducted in controls have suggested that p-tau modulates the link between Aβ and brain atrophy or behavioral changes, whereas animal model literature has demonstrated a synergistic effect between Aβ and p-tau peptides, leading to downstream synaptic and neuronal dysfunctions.

Here, in a longitudinal analysis conducted in amnestic MCI individuals, we tested the hypothesis that the synergism between Aβ aggregation and tau hyperphosphorylation determines progression from amnestic MCI to AD dementia. In this study, we found that amnestic MCI Aβ+/p-tau+ individuals had the highest rate of cognitive decline and progression to dementia, as compared to all other biomarker groups. Remarkably, our regression models confirmed that a synergistic rather than additive effect between Aβ and p-tau determined greater cognitive decline and clinical progression in amnestic MCI Aβ+/p-tau+. Furthermore, we found that only among amnestic MCI Aβ+/p-tau+ individuals, did the baseline values of Aβ and p-tau biomarkers predict cognitive and clinical impairments.

Overall, our results suggest the synergism between Aβ and p-tau as an important element involved in the progression from amnestic MCI to AD dementia. This finding extends previous studies conducted in cognitively normal persons demonstrating that the synergism between Aβ and p-tau determines functional and structural abnormalities. This study revealed that the link between Aβ levels and progression to AD dementia depends on the p-tau status. This finding sheds light on the literature showing conflicting results reporting the association between Aβ and cognition. From a clinical perspective, if replicated, such a synergism has important implications in understanding the dynamics of progression to dementia. From a therapeutic perspective, one can derive important predictions from the existence of a synergistic interaction between Aβ and p-tau in AD. For example, one can predict that therapeutic interventions targeting either Aβ or p-tau pathology might similarly mitigate AD progression. Furthermore, the same synergistic model implies better effectiveness of a combined therapeutic approach targeting both, Aβ and p-tau, pathological pathways.

The Adventurous are Undergoing Enhancement Gene Therapies

As I've been saying for the past couple of years, gene therapies are straightforward enough and cheap enough to carry out that people are doing it, usually quietly, but it is happening. You only have to be connected enough to know a biotechnologist or two with the right skills, as the example here shows. The stage of the adventurous and the self-experimenters is an important part of the development of any new medical technology, helping to overcome institutional reluctance while gathering initial data on how best to approach such treatments in practice. The next part of the process, something that does requires much greater funding and participation from the research and development community, will happen over the next few years; it involves making the therapies more robust, the outcomes more reliable, and assembling the suite of tools and clinics needed for those tasks. That is certainly the goal of BioViva, and as they move forward, others will join them.

There is more than enough evidence for the potential utility of enhancement gene therapies based on producing greater muscle growth and improved metabolism via increased follistatin or myostatin knockout, ranging from numerous animal studies to existing natural human and animal mutants to myostatin antibody trials. There is also considerable interest in telomerase gene therapies, though I'd like to wait for more data on that front before diving in myself, given the potential cancer risk. Once these initial approaches are out there, available, and the methodologies of gene therapy have progressed to the point at which there is reliably comprehensive cell coverage - especially in stem cells, as that will determine how lasting the effect is - then a score of other genes bear further investigation and consideration as targets for enhancement therapies.

While I applaud those who set out to undergo gene therapy today, as their work is necessary to move matters along in this age of overabundant caution and oppressive regulation of every activity, I can't say as I think the fellow here made a good choice of gene. This has the look of a more sophisticated form of the hormone therapies practiced over the past few decades, approaches that really don't have a good impact on aging, and outside of correcting deficiencies are not something that should benefit or is expected to benefit someone in normal health for their age. Increased growth hormone, if anything, is exactly the opposite of what animal and human studies suggest is good for longevity.

Last June at a plastic surgeon's office in Davis, California, at Brian Hanley request, a doctor had injected into his thighs copies of a gene that Hanley, a PhD microbiologist, had designed and ordered from a research supply company. Then, plunging two pointed electrodes into his leg, the doctor had passed a strong current into his body, causing his muscle cells to open and absorb the new DNA. The effort is the second case documented of unregulated gene therapy, a risky undertaking that is being embraced by a few daring individuals seeking to develop anti-aging treatments. The gene Hanley added to his muscle cells would make his body produce more growth-hormone-releasing hormone - potentially increasing his strength, stamina, and life span.

Hanley, 60, is the founder of a one-man company called Butterfly Sciences, also in Davis. After encountering little interest from investors for his ideas about using DNA injections to help strengthen AIDS patients, he determined that he should be the first to try it. "I wanted to prove it, I wanted to do it for myself, and I wanted to make progress," says Hanley of his decision to arrange an experiment on himself. Most gene therapy involves high-tech, multimillion-dollar experiments carried out by large teams at top medical centers, with an eye to correcting rare illnesses like hemophilia. But Hanley showed that gene therapy can be also carried out on the cheap in the same setting as liposuction or a nose job, and might one-day be easily accessed by anyone. In an attempt to live longer, some enthusiasts of anti-aging medicine already inject growth hormone, swallow fullerenes, or gulp megavitamins, sometimes with disregard for mainstream medical thinking. Now unregulated gene therapy could be the next frontier.

Hanley's undertaking has caught the attention of big league scientists. His blood is now being studied by researchers at Harvard University at the laboratory of George Church, the renowned genomics expert. Church says he knows of a handful of other cases of do-it-yourself gene therapy as well. "And there are probably a lot more, although no one is quite sure, since regulators have not signed off on the experiments. This is a completely free-form exercise." At least one additional person who underwent self-administered gene therapy is a U.S. biotech executive who did not want his experience publicly known because he is dealing with the U.S. Food and Drug Administration on other matters. Hanley says he did not secure the approval of the FDA before carrying out his experiment either. The agency requires companies to seek an authorization called an investigational new drug application, or IND, before administering any novel drug or gene therapy to people. "They said 'You need an IND' and I said, 'No, I don't,'" recalls Hanley, who traded emails with officials at the federal agency. He argued that self-experiments should be exempt, including because they don't pose any risk to the public.

So what happens next? The U.S. Food and Drug Administration could get involved, intervening with warning letters or site visits or auditing his ethics board. The plastic surgeon-whose name Hanley wished to keep confidential-could face questions from California's medical board. Companies that supply plasmids might start taking a closer look at who is ordering DNA and what they plan to do with it. Or perhaps authorities will simply look the other way because Hanley experimented on himself. Hanley is proud of what he's done. He created a company, secured patents, made new contacts, identified a gene therapy that has plausible benefits for people, thought in detail about the risks, and offered himself up as a pioneering volunteer.


GSK-3 Inhibitors Can Spur Tooth Regeneration to Fill Cavities

There are a number of very promising lines of work in dental regenerative medicine these days, in regenerating parts of teeth or whole teeth, and in preventing the causes of cavities and gum disease. Here, researchers have developed a comparatively simple approach that greatly increases the normally inadequate regeneration of damaged dentine in teeth. They went on to demonstrate that this can be used as the basis for a treatment to repair large cavities:

Following trauma or an infection, the inner, soft pulp of a tooth can become exposed and infected. In order to protect the tooth from infection, a thin band of dentine is naturally produced and this seals the tooth pulp, but it is insufficient to effectively repair large cavities. Currently dentists use man-made cements or fillings, such as calcium and silicon-based products, to treat these larger cavities and fill holes in teeth. This cement remains in the tooth and fails to disintegrate, meaning that the normal mineral level of the tooth is never completely restored.

However, researchers have proven a way to stimulate the stem cells contained in the pulp of the tooth and generate new dentine - the mineralised material that protects the tooth - in large cavities, potentially reducing the need for fillings or cements. The novel, biological approach could see teeth use their natural ability to repair large cavities rather than using cements or fillings, which are prone to infections and often need replacing a number of times. Indeed when fillings fail or infection occurs, dentists have to remove and fill an area that is larger than what is affected, and after multiple treatments the tooth may eventually need to be extracted. As this new method encourages natural tooth repair, it could eliminate all of these issues, providing a more natural solution for patients.

Significantly, one of the small molecules used by the team to stimulate the renewal of the stem cells included Tideglusib, which has previously been used in clinical trials to treat neurological disorders including Alzheimer's disease. This presents a real opportunity to fast-track the treatment into practice. Using biodegradable collagen sponges to deliver the treatment, the team applied low doses of small molecule glycogen synthase kinase (GSK-3) inhibitors to the tooth. They found that the sponge degraded over time and that new dentine replaced it, leading to complete, natural repair. Collagen sponges are commercially-available and clinically-approved, again adding to the potential of the treatment's swift pick-up and use in dental clinics.


Reviewing the Evidence for PAPP-A as a Target to Modestly Slow Aging in Mammals

Today I'll point out a review of one protein, pregnancy-associated plasma protein-A (PAPP-A), for which levels can be reduced or interactions inhibited in order to slow aging in mice. A decade ago, researchers claimed life extension on a par with calorie restriction in a study of mice lacking PAPP-A. More recently, evidence was assembled to show better thymic and immune function in old mice with this mutation, findings elaborated upon in a later paper. The consensus to date is that this life extension in mice is due to both lowered cancer incidence and slowed aspects of aging, and that insulin-like growth factor 1 (IGF-1) and related insulin metabolism is important in these effects. Cancer incidence is split of as it is generally considered to be only loosely coupled to aging - that it is possible to produce therapies and alterations that affect cancer rate without greatly affecting aging, and possibly vice versa. You might recall some debate along these lines for the life extension produced by rapamycin in mice.

The web of mechanisms and feedback loops that operates within a cell is enormously complex and intricate. The circulating levels of specific proteins are the switches and dials of cellular behavior, and they all influence one another, usually quite indirectly. No alteration can be made in isolation. On the other hand, that means that there are potentially dozens of feasible ways to tamper with any one core mechanism relevant to the ways in which metabolic processes determine natural variations in longevity. The challenge lies less in finding ways to modestly slow aging in laboratory animals, given that there are now scores of methodologies for slowing aging to some degree in various species, and more in understanding exactly why any particular intervention has that effect. Mapping of the links between proteins and genes and various cellular mechanisms proceeds slowly: it is an enormous job. That is one of the reasons why I'm less in favor than many of attempts to alter metabolism to slow aging. A great deal of work is required to gain the understanding needed in order to produce gains that rarely match those of calorie restriction. I'd like to see better outcomes than that in the future.

Insulin and IGF-1 are at the center of those metabolic processes and mechanisms most studied by the research community in the context of natural variations in aging and longevity. So it shouldn't be surprising to find more links uncovered here than for other mechanisms, perhaps. Many methods that slow aging can be attributed to their influence on this slice of metabolism, and the outcomes often look very similar to the beneficially altered metabolic state produced by the practice of calorie restriction. Some decades from now, once the dust has settled and much more of cellular metabolism has been comprehensively mapped, it will be interesting to see just how many of today's long-lived mutant lineages are in fact long-lived because their altered biochemistry involves some facet of the underlying cellular reaction to starvation. Today the map isn't good enough to answer that question all that well. But is this all, PAPP-A and similar methods, worth chasing with major investments in medical research? If you think that calorie restriction mimetics are a good thing, then perhaps. But this isn't the path to rejuvenation after the SENS vision for repair of the causes of aging, and not an approach capable in principle of radical life extension of decades and more. If you aim for small gains, small gains tend to be what you achieve at the end of the day.

PAPP-A: a promising therapeutic target for healthy longevity

The main known function of PAPP-A is to increase local IGF bioavailability through cleavage of inhibitory IGFBPs, in particular IGFBP-4. Indeed, PAPP-A is probably the only physiological IGFBP-4 proteinase. PAPP-A-induced enhancement of local IGF action through proteolysis of IGFBP-4 has been demonstrated in vitro and in vivo in several different systems. Reduced IGF signaling has been associated with longevity and increased healthspan. Therefore, a reduction in PAPP-A proteolytic activity represents a novel approach to indirectly decrease the availability of bioactive IGF. For therapeutic intervention, such a strategy is expected to moderately restrain IGF signaling and hence cause fewer adverse effects compared to direct inhibition by targeting the IGF receptor.

Both male and female PAPP-A knockout (KO) mice on chow diet live 30-40% longer than wild-type (WT) littermates, with no secondary endocrine abnormalities. Circulating levels of growth hormone (GH), IGF-I, glucose, and insulin were not significantly different between PAPP-A KO and WT mice in this study. PAPP-A KO mice also live longer when fed a high fat diet starting as adults. Thus, PAPP-A deficiency can promote longevity without dietary restriction. Furthermore, this extended lifespan is not a secondary consequence of a small body size because PAPP-A KO mice rescued from the dwarf phenotype by enhanced IGF-II expression during fetal development retain their longevity advantage. Finally, conditional knockout of the PAPP-A gene in adult mice also resulted in a 20% extension of lifespan. End-of-life pathology showed delayed occurrence of fatal neoplasias and indicated decreased incidence and severity of conditions with age-related degenerative changes, such as cardiomyopathy, nephropathy, and thymic atrophy in PAPP-A KO mice compared to WT littermates.

Several mouse models with reduced GH-stimulated IGF-I expression by liver and low levels of circulating IGF-I (Snell, Ames dwarf, GH receptor KO) have also been found to have extended longevity. On the other hand, transgenic mice over-expressing GH exhibit a shortened lifespan. It is important to note that PAPP-A KO mice have normal levels of circulating IGF-I (and GH) and their phenotype reflects reduction in local IGF action. Unlike the GH mutant mice that have postnatal growth retardation, deletion of the PAPP-A gene manifests itself early in fetal development as proportional dwarfism. The lifespan extension in the Snell, Ames dwarf, and GH receptor KO models reflects GH tone rather than IGF-I bioavailability.

Low circulating PAPP-A has been associated with adverse effects on placental function and fetal growth in humans. Although the role of PAPP-A in human pregnancy is not understood, PAPP-A is believed to be important for placental development. Therefore, targeting PAPP-A during human pregnancy is not likely to be a viable strategy. The involvement of PAPP-A in normal tissue repair processes also suggests a possible need to suspend PAPP-A targeting temporarily during such conditions. For example, PAPP-A increases bone accretion primarily by increasing IGF bioavailability important for prepubertal bone growth. Fracture repair in PAPP-A KO mice is temporally compromised, but not prevented from normal resolution. Similarly, controlled increases in PAPP-A expression are seen in healing human skin, indicating that wound healing may be delayed as a consequence of PAPP-A targeting.

Experimental evidence is accumulating that inhibition of PAPP-A has the potential to promote healthy longevity. It is clearly advantageous that targeting of PAPP-A has the benefit of a single intervention that affects multiple adverse changes with age, not just a single condition. PAPP-A is present in the extracellular environment, and its activity is therefore amenable to pharmacologic intervention. Strategies to inhibit PAPP-A have recently been developed and tested in experimental models. Rather than the active site of PAPP-A, a unique substrate-binding exosite, critical for proteolytic cleavage of IGFBP-4, is targeted. This efficiently eliminates activity toward IGFBP-4, but does not interfere with cleavage of other possible substrates of PAPP-A. Inhibition will target discrete conditions with increased PAPP-A activity, resulting in moderate restraint of IGF signaling and minimizing side effects. However, much remains to be learned about stages in life at which mice, and possibly humans, are susceptible to improvements in long-term health by manipulation of PAPP-A.

A Profile of UNITY Biotechnology

An accumulation of senescent cells is one of the causes of aging, and periodic removal of senescent cells is therefore one of the foundations for near future rejuvenation therapies. The first generation of these treatments will likely be available via medical tourism within the next couple of years, but we'll be waiting five years or more for comprehensive human data and passage through the regulatory systems of the US and Europe. For those who have been following events in the nascent senescent cell clearance industry, there won't be much that is new in this popular press article on UNITY Biotechnology, but it is nonetheless an interesting read:

In 2011, Jan van Deursen's team at the Mayo Clinic published research showing that when scientists regularly eliminate senescent cells from mice, the animals remain youthful longer; older mice who got similar treatment appeared to stop aging, based on measures of their mobility, muscle mass, and fat storage. When Nathaniel David saw the paper, he knew had to talk to the authors. Within 72 hours, he and Van Deursen were discussing forming a company. "This is my sixth company. You get kind of pattern recognition on things that feel 'druggable.'"

David was part of the team at Kythera Biopharmaceuticals, bought in 2015 by Allergan for $2.1 billion. Kythera's claim to fame was the development of Kybella, a drug for double chins that literally explodes fat cells. While the Food and Drug Administration considers double chins a reasonable therapeutic target for drug development, it doesn't feel the same way about aging. So even though Van Duersen's Mayo Clinic team showed this past February that clearing senescent cells from middle-aged mice led to a 20% increase in average lifespan versus control animals, UNITY has to focus its therapies on certain conditions. Anyway, David bristles at the idea that UNITY is an "anti-aging" company. The claim, he says, implies that biologists have already figured out what controls the fundamental ticking of the human aging clock. They haven't. Meanwhile, David expects UNITY to test its first drug, for osteoarthritis (OA) of the knee, in humans within 18 months.

Right now, patients with OA of the knee typically get cortisone injections into the joint every few months to treat the pain. Those shots appear to temporarily shut down senescent cells' ability to secrete proteins that cause inflammation, which essentially is the immune system turning on normal tissue, resulting in damage and stiffness. UNITY's drug will be delivered similarly through regularly scheduled injections, but would instead trigger the cells' deaths. Since the offending cells would be gone instead of temporarily muted, their injection could be given every year or two. If you had to pick one medical indication or element associated with aging to go after, says Matt Kaerberlein, an expert in the biology of aging at the University of Washington, "osteoarthritis is a great place to be. It's a specific indication, but it's a indication that could have a huge impact of quality of life for a lot of people."

There are concerns about side effects. For one, senescent cells also play a role in preventing cancer: cells can go into senescence to avoid become cancerous, acting as a sort of cancer emergency brake. David says the key is to make sure that UNITY's drugs don't "screw with the emergency brake." In other words, the company's therapies must avoid preventing cells from becoming senescent, and rather just eliminate them once they've gone down that path. Second, senescent cells play a role in healing wounds, and are often recruited to areas in the body where there's been trauma. Research done by Unity cofounder Judith Campisi has shown that in animals without senescent cells, wounds take longer to heal. A challenge facing Unity is figuring out dosing and treatment schedules to ensure that some senescent cells are available to restore tissues.

For David, the serial entrepreneur, the science behind UNITY is simply irresistible. And the excitement in his voice is audible when he talks about people aging in calendar years without deteriorating physically. While David doesn't believe that his company's therapies will radically increase lifespan, he does see an opportunity to profoundly extend "health span" - body part by body part. "Rather than dying at age 83, demented and catheterized in your bed, how'd you like to die at 107 on the tennis court while winning or be killed by a jealous lover at 112? That's in the realm of the possible with this biology."


Addressing Naturalistic Objections to Extending Healthy Human Life Spans

Here I'll point out another of the articles going up at the Life Extension Advocacy Foundation, this time on the topic of the naturalistic fallacy where it occurs in opposition to healthy life extension. Our community would like to build medical therapies that address the causes of aging, thereby ending age-related disease and greatly extending healthy human life spans. It has always surprised me to find that most people, at least initially, object to this goal. It seems perfectly and straightforwardly obvious to me that aging to death, suffering considerably along the way, is just as much a problem to be overcome as any other medical condition that causes pain and mortality. Yet opposition exists, and that opposition is one of the greatest challenges faced when raising funding and pushing forward with research and development of rejuvenation therapies.

When it comes to treating aging as a medical condition the naturalistic fallacy is voiced in this way: aging is natural, what is natural is good, and therefore we shouldn't tamper with aging. If you look around at your houses, your computers, your modern medicine, and consider that such an objection is perhaps just a little late to the game, and hard to hold in a self-consistent manner, then you're probably not alone. Notably, the same objection is rarely brought up when it comes to treating specific age-related diseases, or in the matter of therapies that already exist. People who are uncomfortable about radical changes to the course of aging and who speak out against the extension of human life are nonetheless almost all in favor of cancer research, treatments for heart disease, and an end to Alzheimer's disease. Yet age-related diseases and aging are the same thing, the same forms of damage and dysfunction, only differing by degree and by the names they are given. Objecting to the treatment of aging on naturalistic grounds without also objecting to near all modern medicine is a deeply incoherent position. The whole and entire point of medicine is to defeat the natural causes of pain, debility, and death.

The word 'unnatural' conjures up feelings of doom and dread, and it is unfortunately often used by critics of science as a way to justify their own concerns. It is argued that interfering with the natural order of things is wrong and against nature, and therefore increasing lifespans thanks to scientific advancements is something we should not be doing. From an early age, most of us are taught that 'natural' is good and always preferable. Concepts like 'natural organic food is better,' 'natural remedies are always the best option,' and so on are all deeply ingrained into our culture. With this in mind, it is easy to understand why some people may consider the advanced medicines and next generation therapies science is developing being somehow unnatural.

We have always sought ways to protect our health and extend human lifespan. But there are methods that already existed when we were born, and methods appearing later. Most people would not consider washing their hands, taking medicines, or undertaking surgery as being bad - unnatural or unethical - because we are used to their existence. These are ways to extend life. But we tend to feel anxious when we encounter something new. Part of this reaction is biologically programmed: during human evolution, new things might turn out to be dangerous, and wariness could be a successful strategy. But another part is related to the deficiency of knowledge about the new intervention and the indirect consequences of its application.

In case of need, such as the need to cure a severe and aggressive disease, we welcome even radical interventions like gene therapy, because we know for sure that the alternative is probably death - and nothing can be worse than that. But let's remember that the various aging processes lead to the development of deadly diseases, like cancer, Alzheimer's, Parkinson's, heart disease and stroke, which makes any attempts to bring these processes under medical control highly ethical. A number of researchers are currently debating if aging should be considered a disease or a syndrome itself, and some suggest including aging as a disease under the International Classification of Diseases (ICD-11). If accepted as part of ICD-11 it could create an opportunity for the medical industry to test and register new interventions for addressing the aging processes. This would then allow healthy middle aged patients to use these interventions even in the absence of age-related diseases, in order to prevent or postpone their manifestation.

As so-called life extension technologies are no more than medical technologies focused on preventing age-related diseases at very early stage and sustaining health throughout life, it is obvious that they should be considered in the same way as any other form of medicine. They are no more unnatural than the medicines we already use today. The development of medical technologies, their implementation, and the efforts to make them accessible and affordable to every human being reflect the universal goal of the continuous improvement of health.


Calorie Restriction as a Means to Improve Surgical Outcomes

The long-term response to calorie restriction has long been of interest to the aging research community, and particularly in the past few decades as the tools of biotechnology allowed for a more detailed analysis of the metabolic changes that accompany a reduced calorie intake. A restricted diet extends healthy life spans in near all species tested to date, though to a much greater extent in short-lived species than in long-lived species such as our own. Considerable effort is presently devoted to the development of drugs that can replicate some fraction of calorie restriction - more effort than is merited in my opinion, given that the optimal result for extension of human life span achieved via calorie restriction mimetics will be both hard to achieve safely and very limited in comparison to the gains possible through rejuvenation therapies after the SENS model. Repairing damage within the existing system should be expected to outdo attempts to change the system in order to slow the accumulation of damage, in both efficiency and size of result.

Not everyone is interested in the long term, however. The short term health benefits of calorie restriction appear quickly and are surprisingly similar in mice and humans, given that calorie restriction in mice results in significantly extended life and calorie restriction in humans does not. The beneficial adjustments to metabolism and organ function are for the most part larger and more reliable than similar gains presently achievable through forms of medicine. That is more a case of medical science having a long way to go yet than calorie restriction being wondrous, however. Still, the short term benefits are coming to the attention to wider audience within the research and medical community. For example, calorie restriction and fasting are proving to be useful adjuvant treatments that improve outcomes for cancer patients: you might recall an interview with one of the researchers involved, as well as a paper from a few years back showing that periodic fasting improves recovery of the immune system from the damage caused by chemotherapy. In addition there is good evidence for calorie restriction and fasting to improve the outcomes following surgery, priming the body for the stress of that experience. Researchers have made some inroads in tracing the important mechanisms in this effect, as outlined in the following open access review paper:

Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes

Dietary restriction (DR), or reduced food intake without malnutrition, was found in 1935 to extend lifespan of laboratory rats. Since that time, longevity extension by DR has been demonstrated in numerous experimental organisms from yeast to non-human primates. Fortunately, DR confers other important benefits that do not require long periods of food restriction, including increased resistance to multiple forms of acute stress. One of the biggest planned stressors many people will face in their life is that of major elective surgery, which carries inherent risks of complications. A novel concept in surgical risk mitigation emerging from basic research on DR and aging is dietary preconditioning, or short-term DR lasting one week or less prior to surgery. In rodent models of surgical stress ranging from ischemia reperfusion injury (IRI) to vascular restenosis (intimal hyperplasia), short-term DR or fasting before surgery, followed by a return to normal food intake after surgery, leads to improved outcomes.

Because of the plethora of physiological and molecular changes that occur even upon short-term restriction of a single essential amino acid from the diet, identification of critical downstream mechanisms of DR-mediated protection against surgical stress is challenging. Elucidation of upstream nutrient-sensing pathways such as GCN2 and mTORC1, for which genetic full-body or tissue-specific knockout models are available, has proven a critical step forward. Using experimental designs in which dietary interventions are combined with genetic models lacking upstream nutrient sensors that fail to gain protection upon DR, two major downstream mechanisms involving increased prosurvival insulin signaling and endogenous H2S production have recently been elucidated.

How does the DR-mediated improvement in hepatic insulin sensitivity contribute to protection from hepatic IRI? In addition to regulating energy metabolism, insulin can act as a prosurvival factor via negative regulation of apoptosis. Consistent with this mechanism of action, circulating insulin levels and antiapoptotic signaling are both increased in the hours after liver reperfusion in wild-type mice preconditioned on DR, while this effect is absent in mice with constitutive insulin resistance. Taken together, these data suggest that a major mechanism of DR action is via increased insulin sensitivity prior to an injury, which then facilitates increased prosurvival signaling and reduced hepatocyte apoptosis after injury.

Although toxic at high levels, endogenously produced H2S by one of three evolutionarily conserved enzymes is now recognized to have pleiotropic cytoprotective, anti-inflammatory and vasodilatory effects resulting in cardioprotection and resistance to ischemic injury. H2S also has direct antioxidant properties, and can participate in mitochondrial energy production by donating electrons to the mitochondrial electron transport chain protein SQR, with a potential role in protection from ischemia. Since pharmacological delivery of H2S also protects in models of surgical stress, as well as more broadly in preclinical models of cardiovascular disease, it remains to be seen if supplementation with exogenous sources of H2S, or increased endogenous H2S production through dietary or other means, will ultimately turn out to be more beneficial in the context of surgical stress resistance.

The findings that short-term fasting or restriction of food intake - on the order of days to a week - leads to robust functional benefits in rodents has profound implications for the mechanism of DR action in mammals. Rather than previous notions of DR as an intervention whose benefits accumulate over long periods of time due to reduced calorie intake, DR is now viewed as a rapid adaptation to the mild stress of calorie and/or nutrient deprivation with the potential to protect against many other forms of stress. This new understanding has important practical implications for attempts to leverage DR against clinically relevant endpoints, including planned surgery. If future clinical trials identify brief DR regimens or pharmacological DR mimetics that are safe and effective against the stress and potential complications of surgery, how would this change current preoperative nutritional standards? With few exceptions, there is currently no consensus on what should or should not be eaten up to 1 day prior to surgery, so long as the patient is not suffering from malnutrition.

Currently, the duration of preoperative fasting used as an "anesthetic precaution" in humans is likely too short to tap into DR benefits, while the progressive clinical application of existing nutritional guidelines promotes an alternate although not mutually exclusive concept of increased nutrition immediately prior to surgery. Future clinical trials are required to test the safety, feasibility, and potential efficacy of short-term DR, including extended periods of fasting, to reduce risk of surgical complications and improve outcomes. If successful, this approach has the potential to change the paradigm for preoperative nutritional care based on concepts derived from research into the basic biology of aging.

Attempting to Build a Biomarker of Aging from Standard Blood Test Metrics

Is it possible to assemble a useful biomarker of biological aging from a combination of existing metrics easily obtained via blood tests? This is an open question, but a number of research groups have made the attempt. To be useful, it would have to work at least as well as the DNA methylation biomarkers currently under development. The combination of metrics outlined in this open access paper is a start in that direction, but much more work and validation is needed. A robust, discriminating biomarker that reflects biological age, the level of molecular damage to cells and tissues and consequences thereof, would allow faster development, verification, and improvement of rejuvenation therapies. Without such a tool, it is very slow and expensive to determine the degree to which any particular candidate therapy has beneficial long-term effects on healthy life span. That in turn makes it hard to discard less effective approaches in favor of more effective approaches, and the greater cost means that less progress is made for a given investment in research and development.

The steady increase in human average life expectancy in the 20th century is considered one of the greatest accomplishments of public health. Improved life expectancy has also led to a steady growth in the population of older people, age-related illnesses and disabilities, and consequently the need for prevention strategies and interventions that promote healthy aging. A challenge in assessing the effect of such interventions is 'what to measure'. Chronological age is not a sufficient marker of an individual's functional status and susceptibility to aging-related diseases and disabilities. As has been said many times, people can age very differently from one another. Individual biomarkers show promise in capturing specificity of biological aging, and the scientific literature is rich in examples of biomarkers that correlate with physical function, anabolic response, and immune aging. However, single biomarker correlations with complex phenotypes that have numerous and complex underlying mechanisms is limited by poor specificity.

Moving from a simple approach based on one biomarker at a time to a systems analysis approach that simultaneously integrates multiple biological markers provides an opportunity to identify comprehensive biomarker signatures of aging. Analogous to this approach, molecular signatures of gene expression have been correlated with age and survival, and a regression model based on gene expression predicts chronological age with substantial accuracy, although differences between predicted and attained age could be attributed to some aging-related diseases. The well-known DNA methylation clock developed by Horvath has been argued to predict chronological age. Alternative approaches that aggregate the individual effects of multiple biological and physiological markers into an 'aging score' have also been proposed. These various aging scores do not attempt to capture the heterogeneity of aging. In addition, many of these aging scores use combinations of molecular and phenotypic markers and do not distinguish between the effects and the causes of aging.

Here we propose a system-type analysis of 19 circulating biomarkers to discover different biological signatures of aging. The biomarkers were selected based upon their noted quantitative change with age and specificity for inflammatory, hematological, metabolic, hormonal, or kidney functions. The intuition of the approach is that in a sample of individuals of different ages, there will be an 'average distribution' of these circulating biomarkers that represents a prototypical signature of average aging. Additional signatures of biomarkers that may correlate to varying aging patterns, for example, disease-free aging, or aging with increased risk for diabetes or cardiovascular disease (CVD), will be characterized by a departure of subsets of the circulating biomarkers from the average distribution. We implemented this approach using data from the Long Life Family Study (LLFS), a longitudinal family-based study of healthy aging and longevity that enrolled individuals with ages ranging between 30 and 110 years.

We used an agglomerative algorithm to group LLFS participants into clusters thus yielding 26 different biomarker signatures. To test whether these signatures were associated with differences in biological aging, we correlated them with longitudinal changes in physiological functions and incident risk of cancer, cardiovascular disease, type 2 diabetes, and mortality using longitudinal data collected in the LLFS. Signature 2 was associated with significantly lower mortality, morbidity, and better physical function relative to the most common biomarker signature in LLFS, while nine other signatures were associated with less successful aging, characterized by higher risks for frailty, morbidity, and mortality. The predictive values of seven signatures were replicated in an independent data set from the Framingham Heart Study with comparable significant effects, and an additional three signatures showed consistent effects. This analysis shows that various biomarker signatures exist, and their significant associations with physical function, morbidity, and mortality suggest that these patterns represent differences in biological aging.


Manipulating the Wound Healing Process to Prevent Scarring

While there are some engineered mammalian lineages that can heal small wounds without scarring, further investigations of the biochemistry involved have yet to lead to a robust clinical treatment. Other lines of research are starting to look more promising, however. Here researchers demonstrate early implementations of a methodology that may prove to be the basis for a practical therapy to reduce scar tissue formation in wound healing:

Fat cells called adipocytes are normally found in the skin, but they're lost when wounds heal as scars. The most common cells found in healing wounds are myofibroblasts, which were thought to only form a scar. Scar tissue also does not have any hair follicles associated with it, which is another factor that gives it an abnormal appearance from the rest of the skin. Researchers used these characteristics as the basis for their work - changing the already present myofibroblasts into fat cells that do not cause scarring. "Essentially, we can manipulate wound healing so that it leads to skin regeneration rather than scarring. The secret is to regenerate hair follicles first. After that, the fat will regenerate in response to the signals from those follicles."

The study showed hair and fat develop separately but not independently. Hair follicles form first, and the researchers previously discovered factors necessary for their formation. Now they've discovered additional factors actually produced by the regenerating hair follicle to convert the surrounding myofibroblasts to regenerate as fat instead of forming a scar. That fat will not form without the new hairs, but once it does, the new cells are indistinguishable from the pre-existing fat cells, giving the healed wound a natural look instead of leaving a scar.

As they examined the question of what was sending the signal from the hair to the fat cells, researchers identified a factor called Bone Morphogenetic Protein (BMP). It instructs the myofibroblasts to become fat. This signaling was groundbreaking on its own, as it changed what was previously known about myofibroblasts. "Typically, myofibroblasts were thought to be incapable of becoming a different type of cell, but our work shows we have the ability to influence these cells, and that they can be efficiently and stably converted into adipocytes." This was shown in both the mouse and in human keloid cells grown in culture. These discoveries have the potential to be revolutionary in the field of dermatology. The first and most obvious use would be to develop a therapy that signals myofibroblasts to convert into adipocytes - helping wounds heal without scarring.