Fight Aging! Newsletter, February 5th 2018

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

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  • The Pineapple Fund Donates Millions to the Organ Preservation Alliance and Methuselah Foundation
  • Telomerase Gene Therapy Used to Cure Fibrosis in a Mouse Model
  • Two Recent Review Papers on the Aging of Blood Vessels
  • Aubrey de Grey on Progress and Timescales in Rejuvenation Research
  • The Sizable First Volume of the 2017 Longevity Industry Landscape Overview
  • Senescent Cells Contribute to Vascular Dysfunction and the Biochemistry of Alzheimer's Disease
  • The Infectious Dose of Cytomegalovirus Determines the Degree of Resulting Age-Related Immune Dysfunction
  • Increased Sirt4 Modestly Increases Fly Lifespan
  • Gbp1 Levels Fall with Age, Making Macrophages Less Helpful and More Harmful
  • Thoughts on Mechanisms Linking Body Temperature and Aging
  • Yes, Of Course it is the Case that Life Expectancy at Birth Grew More Slowly in the Second Half of the 20th Century
  • Rapamycin Does Not Interact Favorably with Growth Hormone Receptor Knockout
  • Towards Therapies Based on Klotho
  • Where Next for Cellular Reprogramming and Regenerative Medicine?
  • An Impressive Performance in Clearing Cancer from Mice via Immunotherapy

The Pineapple Fund Donates Millions to the Organ Preservation Alliance and Methuselah Foundation

The anonymous principal of the Pineapple Fund is a long-term holder of bitcoins, one of a number of people who have achieved considerable wealth in this way. Unlike most of the others, this individual holds the - eminently sensible - viewpoint that, after a certain point, the only real use for wealth is to craft a better world. Since the human condition, society included, is determined by technology, crafting a better world largely means supporting the development of new technologies that will allow us to overcome sources of suffering and limitation. In this context, by far the greatest cause of suffering and death in the world is aging.

One of the first donations made by the Pineapple Fund was a 1 million gift to the SENS Research Foundation, to accelerate ongoing work needed for the development of rejuvenation therapies based on periodic repair of the cell and tissue damage that causes aging. Another 1 million was added a little later. More recently, the Pineapple Fund has now given 2 million to the Organ Preservation Alliance and 1 million to the Methuselah Foundation, both deserving organizations in the same network, focused on advancing the state of medical research to help address the causes and consequences of aging.

The Methuselah Foundation should need little introduction for the audience here. It was the original home for the first SENS rejuvenation research projects, back when the budget was tiny and obtaining a five figure donation for the cause was a very big deal. The Methuselah Foundation has since generated the New Organ network of groups and researchers focused on tissue engineering, with the production of whole organs as a goal. Over the years, the foundation has invested in and incubated a number of startup companies such as Organovo (tissue printing), Oisin Biotechnologies (senescent cell clearance), and Leucadia Therapeutics (addressing protein aggregates in the brain). Those efforts have given rise to the Methuselah Fund, now that ever more venture funding is showing interest in the field. The Methuselah Foundation has less of a vocal public face than the SENS Research Foundation, but if you look at any of the activities and initiatives that take place in the broader rejuvenation research community, you'll usually find the Methuselah Foundation is connected in some way, behind the scenes. They play an important role.

The Organ Preservation Alliance is one of the more influential parts of the aforementioned network of groups focused on accelerating progress towards tissue engineered whole organs. Their specific area of interest is in the long-term preservation of large tissue sections. One of the important themes of recent years has been the meaningful signs of progress towards reversible cryopreservation, for example. If organs can be reliably vitrified and thawed with minimal damage, this will greatly simplify the logistics and reduce the costs inherent in both tissue engineering and the present organ donation industry. Being able to put an organ, donated or manufactured, into storage for the long term will change near everything about the way in which the field must presently operate. This isn't just important for the mainstream of medicine, however, as success in reversible cryopreservation will also provide considerable support for the cryonics industry, which is both vital and neglected.

The actions of the Pineapple Fund principal appear to be inspiring others in the cryptocurrency community to make donations of their own, and that, I think, is a useful outcome to see spreading through any community of high net worth individuals - or indeed, any community at all. The worst thing that one can do with wealth is nothing. There are any number of ways in which the world might be improved given a sensible approach to philanthropy, guided by personal principles of what is and is not important.

Telomerase Gene Therapy Used to Cure Fibrosis in a Mouse Model

Maria Blasco's research group has been working on telomerase gene therapy to lengthen telomeres for some years now; they are quite enthusiastic about this approach as a means to treat aging. One can't argue with the data showing extension of mouse life span, nor the results announced today in which induced telomerase activity is shown to reverse fibrosis. We can argue about what is going on under the hood, and whether or not addressing telomere length is in fact tackling the root causes of aging. Perhaps the most important difference between the views of aging outlined in the SENS rejuvenation research proposals and the later Hallmarks of Aging is that the latter places telomere length front and center as being of importance. In the SENS view, telomere length is a secondary marker, a consequence of other forms of damage.

So how can a therapy that induces telomerase activity to lengthen telomeres, something that to my eyes doesn't address root causes of aging, produce significant impact on mouse longevity? Well, there are many proven ways to produce significant gains in mouse longevity that have nothing to do with repairing damage after the SENS model. Calorie restriction, for example, is exactly a slowing of aging, a slowdown of the accumulation of damage, and it produces a larger gain in life span than telomerase gene therapy in mice. It doesn't do that much for human life span, sadly, though it is certainly good for health.

As a general rule we should expect approaches based on manipulating the operation of metabolism to produce comparatively poor effects in humans. We should expect approaches based on repairing the root cause cell and tissue damage of aging to produce better results in humans. Judging from the data in mice obtained to date - let us say comparing senolytics to remove senescent cells, one of the root causes of aging, with telomerase gene therapy, and with calorie restriction - all of the methodologies produce results that are in the same broad ballpark in terms of life span gained, in the 20-60% range.

The next decade will settle the critical question of what a rejuvenation therapy can achieve for human life expectancy in older individuals. The data will primarily involve senolytic treatments, as those the only one ready to go into trials right now. We can then compare that data with what is known of calorie restriction in humans, which is to say little gain in life span, even while delivering measurable health benefits. But for now, the research community only has data for direct comparison in examples of what is thought to be the less effective way forward, slowing aging by the adjustment of metabolism. That data exists for calorie restriction and growth hormone receptor dysfunction only.

It is far from clear that one can lump telomase gene therapy into either the bucket holding calorie restriction (slowing aging) or the bucket holding senolytics (damage repair to reverse aging). It may need a bucket of its own, for approaches that force a reversal in a secondary or later issue in aging, while leaving the underlying damage to continue to fester. Naively, one might guess that this will be better than slowing aging, and worse than repairing root causes. But the data isn't there in humans, and the entire issue is enormously complicated by the fact that all of the methods examined to date are far less capable of extending life span for long-lived species such as our own - which may or may not be the case, or the case to the same degree, for repair-based approaches.

But let us consider what is going on in this study. The mice were given lung fibrosis via bleomycin treatment, a chemotherapeutic that causes lung inflammation. It is known that inflammation of lung tissue produces the disruption of regenerative processes that result in fibrosis, the inappropriate construction of scar-like connective tissue that degrades normal tissue function. Research of the past few years points squarely towards senescent cells and their inflammatory signaling as the primary cause of this issue. There is good evidence for the removal of senescent cells to turn back fibrosis. Toxic chemotherapeutics like bleomycin cause cells to become senescent, putting them under enough stress to trigger that irreversible state change.

In humans with lung fibrosis who exhibit shorter average telomere length, replicative senescence may be the more important source of lingering senescent cells. Senescence occurs in somatic cells when they reach the Hayflick limit, the end of a countdown in which each cell division results in shorter telomeres. Shorter average telomere length implies that stem cells are not keeping up with delivering fresh new cells with long telomeres, and this may produce all sorts of systematic changes in the function, inflammatory state, and signaling environment of a tissue.

So the question here is how telomerase induction helps this situation. The researchers believe their gene therapy vector preferentially targets lung cells, so we can probably put aside consideration of possible immune system effects, such as more energetic clearance of senescent cells. One possibility is that telomerase induction in senescent cells mutes the inflammatory, harmful signaling they produce, the senescence-associated secretory phenotype (SASP). Another possibility is that it pushes senescent cells into self-destruction, either directly, or perhaps indirectly through other changes to the overall signaling environment in the tissue, particularly the contributions made by stem cells. Past work has suggested that some of the benefits in mice given telomerase gene therapy are due to renewed, more youthful stem cell activity in tissue maintenance. Regardless, I think that, given other work on fibrosis and cellular senescence, one has to look at this with a focus on senescent cells.

Researchers cure lung fibrosis in mice with a gene therapy that lengthens telomeres

Idiopathic pulmonary fibrosis is a potentially lethal disease associated with the presence of critically short telomeres, currently lacking effective treatment. Researchers have succeeded in curing this disease in mice using a gene therapy that lengthens the telomeres. Telomeres are protein structures located at the ends of each chromosome; like caps, they protect the integrity of the chromosome when the cell divides. But telomeres only fulfill their protective function if they are long enough; when they shorten too much, the damaged cells cease to divide preventing tissue regeneration. Short telomeres are associated with ageing - as age increases, cells accumulate more divisions and more telomeric shortening - and also with several diseases. Pulmonary fibrosis is one of them.

In lung fibrosis, the lung tissue develops scars that cause a progressive loss of respiratory capacity. Environmental toxins play an important role in its origin, but it is known that there must also be telomeric damage for the disease to appear. Patients with pulmonary fibrosis have short telomeres whether the disease is hereditary - it runs into the family - or not. The most likely explanation is that when the telomeres become too short, the damaged cell activates a 'repair program' that induces scar formation that leads to fibrosis.

Researchers decided to address the problem about five years ago, starting with the development of an animal model that faithfully reproduces the human disease. The most widely used model until then was to apply bleomycin into the mouse lungs to induce damage, in an attempt to reproduce the environmental insult. However, in these animals the disease goes into remission in a few weeks and there is not telomere shortening. The researchers sought after a mouse model in which the environmental damage synergized to that produced by short telomeres, that is what happens in human pulmonary fibrosis. They succeeded in 2015.

The treatment consisted of introducing the telomerase gene into the lung cells using gene therapy. The researchers first modified a virus innocuous to humans (known as vectors) so that their genetic material incorporated the telomerase gene, and then injected those vectors into the animals. The basis of this work is the hypothesis that age-associated diseases can be treated by targeting the molecular and cellular processes of ageing, specifically telomere shortening. In 2012, the researchers generated mice that not only lived longer but also showed improved health by treating them with telomerase. Their work since then has aimed to develop this therapy to specifically treat age-associated diseases and telomere syndromes.

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII).

AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.

Two Recent Review Papers on the Aging of Blood Vessels

Today I'll point out a couple of recently published open access papers that discuss aspects of arterial aging. The age-related decline of blood vessel structure and function is one of the more important aspects of aging, given that it is at present a largely one-way road to cardiovascular disease and death. Despite the efforts of the research community over past decades, which have included the noteworthy success story of statins, and an ongoing reduction in cardiovascular mortality rates, this remains the principal cause of age-related death in humans. To a first approximation, old humans die when the heart or blood vessels fail. The many other age-related causes of death taken together make up a minority of overall late-life mortality.

Perhaps the most important aspect of blood vessel aging is loss of elasticity. The stiffening of major blood vessels is enough on its own to break the feedback mechanisms that control blood pressure, causing progressively worsening hypertension. Increased blood pressure causes the heart to become larger and weaker, and also increases the rate at which pressure-related damage and blood vessel rupture occurs in more delicate tissues. Stiffening of blood vessels is probably primarily caused by cross-linking in the extracellular matrix, but evidence suggests that senescent cell accumulation and the inflammation generated by these cells also plays a role. These errant cells promote calcification in blood vessel walls, which can also contribute to loss of elasticity. There are also other mechanisms to consider, such as disruption of the normal processes by which blood vessel smooth muscle controls dilation and constriction of blood vessels - separately from stiffening, that can produce similar problems in regulation of blood pressure.

Rising blood pressure on its own is bad, and will ultimately cause death via heart failure. This is made much worse, however, by the progression of atherosclerosis. This is the generation of fatty deposits that narrow and weaken blood vessel walls: high blood pressure plus weakened blood vessels is a recipe for a fatal rupture. Even without that, the fat deposits become unstable and can break off inside the blood vessel to produce a fatal blockage, a process that again is accelerated by higher blood pressure. Atherosclerosis is the result of an unfortunate inflammatory feedback loop. Lipids become oxidatively damaged in ever greater amounts with advancing age, enter the bloodstream, and then irritate the blood vessel walls. Cells respond with an inflammatory response that draws in macrophages to clean up the unwanted lipids, but the macrophages can become overwhelmed and die. That in turn creates debris that calls in more macrophages, generates a larger inflammatory response, and makes the problem worse. The atherosclerotic plaques in aged blood vessels are inflamed graveyards of countless cells, surrounded by ever more cells in the process of adding their corpses to the mass.

In the SENS rejuvenation research viewpoint, all of these problems can be addressed with suitable forms of repair, granting natural repair processes enough breathing room to fix the remainder. Cross-links can be removed via suitable cross-link breakers, pharmaceuticals current in the early stages of development in programs such as that running at the Spiegel Lab at Yale. Senescent cells can be cleared out via senolytic therapies, presently under development by a number of companies. The various forms of damaged lipid, such as 7-ketocholesterol, can be identified and small molecule drugs developed to safely break them down. Many of the errant macrophages crowding around plaques can be targeted and removed to stop them making matters worse, as they have become senescent and can be targeted with senolytics. All of these are plausible near future treatments.

The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis

Atherosclerosis is the most significant human health problem globally. We know today that the disease does not follow a simple, unidirectional progression, and is determined by a myriad of pathways, control mechanisms, and repair processes; these encompass multiple inflammatory molecules, bone marrow (BM)-derived progenitor cells, a range of immune cells such as specific monocyte subpopulations, genetic mutations, and epigenetic modifications among numerous other participants both known and those yet to be discovered. Ultimately, however, the clinical result for an immensely large number of individuals is the formation and growth of vascular lesions with the potential to rupture, leading to life-threatening conditions. It is imperative to continue to evolve technological strategies to both predict and detect the formation, progression, and clinical status of these atherosclerotic plaques, while additional details are elucidated regarding the process of disease progression.

One example of important progress has been made in the control of inflammation when inflammation is no longer promoting repair, but instead has taken a damaging role for the artery. It was recently reported that a monoclonal antibody against IL1-beta, when injected systemically to patient with cardiovascular disease and high inflammatory index, is capable of reducing risk for coronary events, even with already reduced lipids and had no further effect on lipid levels. The role of inflammation is increasingly established in the progression of arterial lesions, and it is useful to consider inflammation in the context of arterial homeostasis.

Arterial repair is triggered and controlled by molecules that belong to inflammatory pathways. However, as was hypothesized and subsequently demonstrated in an animal model, the progression of atherosclerotic inflammation is modulated by the presence or the absence of an efficient repair process. In the presence of BM vascular progenitor cells capable of arterial repair, the artery heals and inflammatory signals subside and vanish. However, reductions in the availability of BM-derived vascular progenitor cells occurring as a consequence of aging or genetic susceptibility (exhaustion or dysfunction) result in a lack of arterial healing.

These reductions can occur either because repair-capable cells are no longer produced effectively by the BM, because the produced cells have become dysfunctional, or a combination thereof. Consequently, inflammatory signals do not subside and vanish, and indeed are heightened to the point where they attract and support monocytes/macrophages and other immune competent cells that further enhance arterial injury. Hence, the maintenance of arterial homeostasis is a complex process that must balance injuries to the arterial wall, inflammatory processes required for triggering and supporting arterial repair, and the renewal of BM-derived vascular progenitor cells that are necessary for such repair.

The Role of MicroRNAs in Arterial Stiffness and Arterial Calcification

Arterial stiffness is a characteristic feature of normal arterial aging, but is also associated with accelerated cardiovascular disorders. Another age-related process is arterial calcification, which in turn is a known risk predictor that increases morbidity and mortality in cardiovascular diseases. MicroRNAs (miRNAs) are small non-coding RNAs that downregulate their target gene expression post-transcriptionally. They are widely studied in recent years and their role in cardiovascular dysfunction is to some extent revealed. Identification of over- or underproduction of miRNAs could be therapeutic targets for prevention and treatment of vascular diseases.

Arterial stiffness results from complicated interactions between multiple components of the vessel wall, including extracellular matrix (ECM) composition, vascular smooth muscle cell (VSMC), and endothelial dysfunction. Collagen and elastin are the most important structural proteins of ECM and key regulators of arterial stiffness as they are responsible for blood vessels' strength and elasticity. Reconstruction of ECM, notably increased levels of aberrant types of collagen and reduction of elastin, appears to be the most important mechanism contributing to arterial stiffness. Matrix metalloproteases (MMPs) are endopeptidases which degrade all kinds of ECM proteins. Thus they play a significant role in arterial stiffness via regulating collagen and elastin levels in ECM.

Moreover, advanced glycation end products (AGEs) contribute to arterial stiffness through cross-linking with ECM proteins, including collagen, which reduces vessel's flexibility. Furthermore, many hormones and cytokines are involved in aortic stiffness, such as angiotensin II (Ang II) which promotes arterial stiffness through regulating signaling pathways that result in altered ECM accumulation and increased vascular tone. Apart from structural abnormalities, VSMC proliferation, migration and calcification, as well as impaired endothelium-dependent dilation through paracrine molecules such as nitric oxide (NO) and endothelin are, also, implicated in the development of arterial stiffness.

Extensive research during the last decade confirmed the association of miRNAs with cardiovascular diseases. MiRNAs seem to play a significant role in arterial stiffness and calcification through modulating critical pathways and molecules such as TGF-β and BMP signaling, Ang II, MMP activity, Runx, and phenotypic switch of VSMC. Thus, they may be used as therapeutic targets or diagnostic markers in the future to decrease arterial stiffness and prevent the development of cardiovascular diseases. However, it is more than obvious that the molecular biology and pathophysiology is very complex. Many miRNAs might have the same target gene (e.g., Runx2 is suppressed by miR-30b-c but enhanced by miR-32), while a single miRNA might exert multiple functions by targeting more than one genes and affecting different pathways with opposing results (e.g., miR-29, miR-19b and their role in fibrosis). Futhermore, miR-145, one of the most important miRNAs in cardiovascular pathophysiology, decreases arterial stiffness by inhibiting TGF-β signaling while, on the contrary, TGF-β activates miR-145 to promote the contractile phenotype of VSMCs and reduce arterial stiffness as well. Targeting TGF-b through miR-145 might have controversial results. To conclude, additional clinical and laboratory research should be continued for the establishment of miRNAs as treatment targets and biomarkers of cardiovascular diseases.

Aubrey de Grey on Progress and Timescales in Rejuvenation Research

Aubrey de Grey of the SENS Research Foundation maintains an active schedule of presentations, and the interview here is one of a series of recent discussions in which he talks about timelines, funding, and progress in recent years. We're in the midst of a tipping point of sorts, as the SENS view of rejuvenation research gathers more attention and legitimacy in the eyes of the public and various sources of funding. Senolytic therapies to clear senescent cells are well into the first stages of clinical development, with new compelling data for cellular senescence to contribute to specific age-related diseases arriving every month now. Targeting senescent cells for destruction was one of the strategies that de Grey started to advocate all the way back in 2002, when the research community was much less welcoming of any discussion of the treatment of aging as a medical condition, and there was little to no funding for such approaches despite the extensive supporting evidence. It doesn't hurt to be proven right when it comes to reinforcing an agenda.

What is the future timeline for the advent of rejuvenation therapies sufficiently effective to grant a few decades of additional healthy life, and substantially rescue aged people from the immediate consequences of high levels of cell and tissue damage? In one sense we can put together a decently robust timeline for SENS research and development and estimate ten years to get to robust mouse rejuvenation in the laboratory, followed by a further ten years to push the first implementations into the clinic. We can feel fairly good about that, and indeed that planning has been carried out at the Methuselah Foundation and later the SENS Research Foundation several times over the past fifteen years. But that best possible pace of progress is entirely dependent on sufficient funding, 100 million or more each year, as well as the rapid cooperation of regulatory bodies. Both of these are sticky, complicated persuasion and human interaction problems. Thus no-one can predict how long it will take to (a) bootstrap SENS rejuvenation research to the necessary funding levels and (b) solve or work around the roadblock to the treatment of aging set up by the FDA and other regulatory bodies sufficiently well to allow rapid clinical implementation of therapies.

We should be optimistic, however, given that this does boil down to persuasion and funding as the limiting factors. That the science is a relatively clear road, and that the delay is all a matter of gathering sufficient support, means that everyone and anyone can help to accelerate progress towards the medical control of aging, and an end to age-related disease. It doesn't require years of schooling to support a field of medical research as a patient advocate or a fundraiser or an entrepreneur. When interested scientists with promising plans are limited entirely by a lack of funding, we can all step up to make a difference. That has happened already: it is possible to look back at the fifteen year history of SENS advocacy and research, and track its progress from an idea with zero funding to the existence of several non-profit foundations devoting millions in philathropic funding every year to the challenge. Our community achieved a great deal over the course of the early, challenging years, and that success can and will continue, with it becoming ever easier to raise ever more funding for research and development.

Anti-Aging Pioneer Aubrey de Grey: "People in Middle Age Now Have a Fair Chance"

Your foundation is working on an initiative requiring 50 million in funding-

Well, if we had 50 million per year in funding, we could go about three times faster than we are on 5 million per year.

And you're looking at a 2021 timeframe to start human trials?

That's approximate. Remember, because we accumulate in the body so many different types of damage, that means we have many different types of therapy to repair that damage. And of course, each of those types has to be developed independently. It's very much a divide and conquer therapy. The therapies interact with each other to some extent; the repair of one type of damage may slow down the creation of another type of damage, but still that's how it's going to be. And some of these therapies are much easier to implement than others. The easier components of what we need to do are already in clinical trials - stem cell therapies especially, and immunotherapy against amyloid in the brain, for example. Even in phase III clinical trials in some cases. So when I talk about a timeframe like 2021, or early 20s shall we say, I'm really talking about the most difficult components.

What recent strides are you most excited about?

Looking back over the past couple of years, I'm particularly proud of the successes we've had in the very most difficult areas. If you go through the seven components of SENS, there are two that have absolutely been stuck in a rut and have gotten nowhere for 15 to 20 years, and we basically fixed that in both cases. We published two years ago in Science magazine that essentially showed a way forward against the stiffening of the extracellular matrix, which is responsible for things like wrinkles and hypertension. And then a year ago, we published a real breakthrough paper with regard to placing copies of the mitochondria DNA in the nuclear DNA modified in such a way that they still work, which is an idea that had been around for 30 years; everyone had given up on it, some a long time ago, and we basically revived it.

What do you think are the biggest barriers to defeating aging today: the technological challenges, the regulatory framework, the cost, or the cultural attitude of the "pro-aging" trance?

One can't really address those independently of each other. The technological side is one thing; it's hard, but we know where we're going, we've got a plan. The other ones are very intertwined with each other. A lot of people are inclined to say, the regulatory hurdle will be completely insurmountable, plus people don't recognize aging as a disease, so it's going to be a complete nonstarter. I think that's nonsense. And the reason is because the cultural attitudes toward all of this are going to be completely turned upside down before we have to worry about the regulatory hurdles. In other words, they're going to be turned upside down by sufficiently promising results in the lab, in mice. Once we get to be able to rejuvenate actually old mice really well so they live substantially longer than they otherwise would have done, in a healthy state, everyone's going to know about it and everyone's going to demand - it's not going to be possible to get re-elected unless you have a manifesto commitment to turn the FDA completely upside down and make sure this happens without any kind of regulatory obstacle.

I've been struggling away all these years trying to bring little bits of money in the door, and the reason I have is because of the skepticism as to regards whether this could actually work, combined with the pro-aging trance, which is a product of the skepticism - people not wanting to get their hopes up, so finding excuses about aging being a blessing in disguise, so they don't have to think about it. All of that will literally disintegrate pretty much overnight when we have the right kind of sufficiently impressive progress in the lab. Therefore, the availability of money will also open up. It's already cracking: we're already seeing the beginnings of the actual rejuvenation biotechnology industry that I've been talking about with a twinkle in my eye for some years.

I'm sure you hate getting the timeline question, but if we're five years away from this breakthrough in mice, it's hard to resist asking - how far is that in terms of a human cure?

When I give any kind of timeframes, the only real care I have to take is to emphasize the variance. In this case I think we have got a 50-50 chance of getting to that tipping point in mice within five years from now, certainly it could be 10 or 15 years if we get unlucky. Similarly, for humans, a 50-50 chance would be twenty years at this point, and there's a 10 percent chance that we won't get there for a hundred years.

You famously said ten years ago that you think the first person to live to 1000 is already alive. Do you think that's still the case?

Definitely, yeah. I can't see how it could not be. Again, it's a probabilistic thing. I said there's at least a 10 percent chance that we won't get to what I call Longevity Escape Velocity for 100 years and if that's true, then the statement about 1000 years being alive already is not going to be the case. But for sure, I believe that the beneficiaries of what we may as well call SENS 1.0, the point where we get to Longevity Escape Velocity, those people are exceptionally unlikely ever to suffer from any kind of ill health correlated with their age. Because we will never fall below Longevity Escape Velocity once we attain it.

Could someone who was just born today expect-

I would say people in middle age now have a fair chance. Remember - a 50/50 chance of getting to Longevity Escape Velocity within 20 years, and when you get there, you don't just stay at biologically 70 or 80, you are rejuvenated back to biologically 30 or 40 and you stay there, so your risk of death each year is not related to how long ago you were born, it's the same as a young adult. Today, that's less than 1 in 1000 per year, and that number is going to go down as we get self-driving cars and all that, so actually 1000 is a very conservative number.

The Sizable First Volume of the 2017 Longevity Industry Landscape Overview

Over on the other side of our still quite modestly sized longevity science community you will find the network that includes Deep Knowledge Ventures, the Biogerontology Research Foundation, and the Aging Analytics Agency, source of the report I'll point out today. "Other side" is a relative term; it isn't far, and you'll recognize many of the names as also being involved in the US research and advocacy ventures more often mentioned here. Portions of our community have long pursued an interest in mapping the initiatives, people, and funding involved in aging research; see the International Aging Research Portfolio, for example. As the fields of geroscience and rejuvenation research have solidified and gathered increasing support, producing an overview of research aimed at the treatment of aging has become a sizable task. That point is well illustrated by the large first volume of the Longevity Industry Landscape Overview series, to be followed up by another four volumes in 2018, and then, if I understand the intent correctly, to be updated yearly going forward. It represents an imposing amount of work, and those involved are to be thanked for their dedication.

This sort of undertaking might be viewed as the building of a foundation, laying a part of the groundwork needed for large-scale investment in the future, particularly from governments and other entities capable of devoting enormous resources to a task (albeit usually clumsily, wastefully, and late). Organizations of that nature tend not to move at all until the topic at hand is buried beneath paper, committees, and years of consideration. All that the relevant functionaries know comes from digests and reports such as the Longevity Industry Landscape Overview, not first-hand understanding. At present the industry of treating aging is just moving out of the laboratory and into the stage of startup companies and handshake deals on investment, of funds whose principals can educate themselves on the science, and of people willing to make leaps of faith and risk. Somewhere in the future, that will slow down and become far more conservative; far greater sums will be moved around as treatments to modestly slow aging and treatments to repair the damage of aging move into the mainstream medical system.

Regarding the science, the first volume quoted here is a set of disparate views on how to proceed, from the pharmaceutical metabolic manipulation to slow aging that characterizes the geroscience community to the SENS vision of regenerative medicine applied to aging, the periodic repair of the cell and tissue damage that causes aging. There is no integration between these different paths ahead, because there really can't be; the purpose is to show the diversity of opinions in the context of a young and rapidly growing industry, not smooth over the sizable differences and many disagreements on the best approach to take. In the years ahead, the evidence from studies in mice and humans will guide the way. The best approaches will stand out and be taken forward to the clinic - just so long as we, the advocates, manage to argue well and raise sufficient philanthropic funding to allow the most promising studies to be carried out in the first place. Standing aside and letting matters progress without that intervention isn't an option, as it only leads to years of unnecessary delay.

Longevity industry systematized for first time

For scientists, policy makers, regulators, government officials, investors and other stakeholders, a consensus understanding of the field of human longevity remains fragmented, and has yet to be systematized by any coherent framework, and has not yet been the subject of a comprehensive report profiling the field and industry as a whole by any analytical agency to date. Experts on the subject of human longevity, who tend arrive at the subject from disparate fields, have failed even to agree on a likely order of magnitude for future human lifespan. Those who foresee a 100-year average in the near future are considered extreme optimists by some, while others have even mooted the possibility of indefinite life extension through comprehensive repair and maintenance. As such the longevity industry has often defied real understanding and has proved a complex and abstract topic in the minds of many, investors and governments in particular.

A report entitled 'The Science of Longevity', standing at almost 800 pages in length, seeks to rectify this. Part 1 of the report ties together the progress threads of the constituent industries into a coherent narrative, mapping the intersection of biomedical gerontology, regenerative medicine, precision medicine, and artificial intelligence, offering a brief history and snapshot of each. Part 2 lists and individually profiles 650 longevity-focused entities, including research hubs, non-profit organizations, leading scientists, conferences, databases, books and journals. Infographics are used to illustrate where research institutions stand in relation to each other with regard to their disruptive potential: companies and institutions specialising in palliative technologies are placed at the periphery of circular diagrams, whereas those involved with more comprehensive, preventative interventions, such as rejuvenation biotechnologies and gene therapies, are depicted as central.

Since these reports are being spearheaded by the UK's oldest biomedical charity focused on healthspan extension, the Biogerontology Research Foundation is publishing them online, freely available to the public. While the main focus of this series of reports is an analytical report on the emerging longevity industry, the reports still delve deeply into the science of longevity, and Volume I is dedicated exclusively to an overview of the history, present and future state of ageing research from a scientific perspective. Volume 2, is set to be published shortly thereafter, and will focus on the companies and investors working in the field of precision preventive medicine with a focus on healthy longevity, which will be necessary in growing the industry fast enough to avert the impending crisis of global aging demographics.

These reports will be followed up throughout the coming year with Volume 3 ("Special Case Studies"), featuring 10 special case studies on specific longevity industry sectors, such as cell therapies, gene therapies, AI for biomarkers of aging, and more, Volume 4 ("Novel Longevity Financial System"), profiling how various corporations, pension funds, investment funds and governments will cooperate within the next decade to avoid the crisis of demographic aging, and Volume 5 ("Region Case Studies"), profiling the longevity industry in specific geographic regions.

Longevity Industry Landscape Overview 2017, Volume 1: the Science of Longevity (PDF)

The greatest problem threatening global economic prosperity and social stability is demographic aging. The only sustainable solution is to extend healthy lifespan (healthspan). Clearly it would be desirable to add life to our years rather than merely years to our lives. But few are aware that health span extension is becoming routine in the laboratory. Scientific breakthroughs have demonstrated up to 30% increased healthspan extension in mice, and much more in non-mammalian model organisms by various pharmacological, environmental, and genetic interventions. In recent years, scientists have elucidated the fundamental mechanisms or hallmarks of aging, opening the field of geroscience - the understanding and manipulation of the fundamental biological processes in age-related disease.

The widest ceiling over the aspirations of geroscience has always been the inextricability of disease from aging and the inextricability of aging from human metabolism, which, being so complex and integral to our day-to-day functioning, can only be amended rather than reconstructed. This limits us because it robs us of the most obvious approach to radical life extension: radical interference in human metabolism. For just as we might like to be able to alter a car's inner workings so that they inflict less wear and tear, so too might we like to be able to somehow rearrange metabolism so that it inflicts less wear and tear on body tissues.

Sadly this is not an option. While subtle interventions in areas such as calorie restriction mimetics hold some promise to appreciably increase life expectancy, anything amounting to a successful radical intervention in metabolism which radically extends life span is inconceivable for the foreseeable future for the above reasons. This brings us to the alternative approach to vehicle longevity: repair and maintenance. Which in human terms means the continuous restoration of human tissues, irrespective of the various processes that age them.

These two approaches differ starkly. The former could be thought of as like meddling with the inner mechanisms of a clock, cogs and all, in order to slow it down. The latter could be imagined as forcing back the hands of a clock, setting back the progress, while inner clockwork, the process, remains unaffected. In human terms 'setting back the hands' means taking knowledge obtained by geroscience, fashioning it into a damage report and devising a repair strategy. And just as setting back a clock does not require the same extensive knowledge of horology as would be involved with meddling with the clockwork, nor does the restoration of aging tissue require an unfeasibly extensive knowledge of geroscience, only enough to enumerate the manifest differences between old and young tissue. So could we then aspire to repair these enumerated damages comprehensively enough and rapidly enough to appreciably postpone disease? In other words might there be an extent to which we can afford to allow aging to proceed as it normally does while simultaneously clearing up the damage it leaves behind, kicking the can disease down the road?

We are in effect describing the application of regenerative medicine to aging. Regenerative medicine is an area of biotechnology which aims to restore damaged tissues and organs. So why not tissues and organs damaged by the miscellaneous ravages of age?

Senescent Cells Contribute to Vascular Dysfunction and the Biochemistry of Alzheimer's Disease

Researchers here make an effort to link the age-related accumulation of senescent cells in vascular tissue with some of the better known biochemistry of Alzheimer's disease. Progressive vascular dysfunction is an important component of aging: loss of elasticity; failure to regulate blood pressure; failing constriction and dilation; the the corrosive growth of fatty atherosclerotic plaques that weaken and narrow blood vessels; increased amyloid deposition in blood vessel walls. In the brain particularly, failure to deliver sufficient oxygen and nutrients via the vascular system is a notable contributing factor in the onset of dementia, and a sizable fraction of Alzheimer's patients also exhibit full-blown vascular dementia.

Recent studies have suggested that senescent cells have a larger role in vascular aging than was previously assumed, contributing to most of the line items noted above, and this open access paper continues that theme. One of the more interesting points of focus here is the generation of amyloid-β, a protein that accumulates in Alzheimer's disease, in the vascular system, both inside and outside the brain. This appears to take place to a greater degree in senescent cells. It will be a most interesting new direction for Alzheimer's research should further investigations find that senescent cells are a significant source of amyloid. Given the low cost of senolytic drug candidates, someone should set up an exploratory trial.

Epidemiological, experimental, and clinical studies have suggested that age-related cerebrovascular dysfunction plays a critical role in the pathogenesis of dementia, including Alzheimer's disease (AD). Amyloid β (Aβ), the main constituent of amyloid plaques and a key pathogenic factor in AD, has detrimental effects on cerebral blood vessels resulting in disruption of homeostatic function of the cerebrovascular endothelial cells. The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs).

Cellular senescence is an important contributor to aging and age-related diseases. Prior studies provided evidence that processing of endogenous APP is down-regulated in senescent human fibroblasts, but the effects of senescence on APP expression and processing in vascular endothelium have not been studied. APP is highly expressed in endothelium and can be processed by two major proteolytic pathways. In the non-amyloidogenic pathway, APP is cleaved by α-secretase thereby generating soluble APPα (sAPPα), a well-known anticoagulant, neurotrophic, and neuroprotective molecule. In contrast, amyloidogenic processing of APP sequentially driven by β-site APP cleaving enzyme (BACE1) and γ-secretase generates cytotoxic Aβ. Under pathological conditions, β-processing of APP is activated therefore increasing production of Aβ. Importantly, inhibition of BACE1 could prevent or reduce the accumulation of Aβ in the brain, thereby reducing AD-related pathology. Not surprisingly, inhibitors of BACE1 are currently being developed for the treatment of AD.

Taken together, the results of the present study suggest that reduced APP expression contributes to down-regulation of sAPPα in senescent brain microvascular endothelium. Increased BACE1 expression and Aβ production suggest that senescence promotes β-processing of APP. Treatment with a BACE1 inhibitor is beneficial for senescent human BMECs. This effect is mediated by shifting of APP processing towards non-amyloidogenic pathway. The present study also reports a novel observation regarding the detrimental effects of Ang II on α-processing of APP by activation of AT2R in senescent human BMECs. Given the fact that the cleavage products of APP play an important role in vascular homeostasis, we propose that increased Aβ production together with loss of sAPPα are previously unrecognized mechanisms of cerebral microvascular endothelial dysfunction induced by senescence and Ang II. Our findings support the concept that pathological expression and processing of APP in senescent cerebrovascular endothelium may play an important role in pathogenesis of cerebral amyloid angiopathy and AD.

The Infectious Dose of Cytomegalovirus Determines the Degree of Resulting Age-Related Immune Dysfunction

Here researchers show that, in mice at least, a greater infectious dose of cytomegalovirus (CMV) causes a larger degree of age-related immune dysfunction. This is a useful paper that might go some way to answering one class of objection to the existing data on the contribution of CMV to immune system aging, in that not everyone who shows the markers of infection is impacted to the same degree. It seems that the level of exposure may be an important factor. The evidence for CMV to be a major issue for immune health is quite compelling: near everyone is infected by the time they are old; the immune system cannot effectively clear CMV; older people are characterized by a rapid increase in the proportion of immune cells uselessly specialized to CMV, and thus unable to contribute to any of the other responsibilities of the immune system.

The best way forward towards effective therapies is probably some form of targeted destruction of these cells, perhaps augmented by a cell therapy to deliver fresh immune cells to renew the defenses more rapidly than would otherwise be the case. There are groups working on vaccines or other medical approaches to clearing CMV, but my impression has been that this won't really help older people who are already greatly impacted: the degraded state of the immune system will remain, and must still be addressed separately. The researchers here think that clearing out the virus may be useful enough to try, however. The question is always the size of the resulting benefit, and it is unlikely that any method other than trying it out will give an acceptably robust answer in an acceptably short period of time.

The relationship between human cytomegalovirus (HCMV) infections and accelerated immune senescence is controversial. Whereas some studies reported a CMV-associated impaired capacity to control heterologous infections at old age, other studies could not confirm this. We hypothesized that these discrepancies might relate to the variability in the infectious dose of CMV occurring in real life. Here, we investigated the influence of persistent CMV infection on immune perturbations and specifically addressed the role of the infectious dose on the contribution of CMV to accelerated immune senescence.

We show in experimental mouse models that the degree of mouse CMV (MCMV)-specific memory CD8+ T cell accumulation and the phenotypic T cell profile are directly influenced by the infectious dose, and data on HCMV-specific T cells indicate a similar connection. Detailed cluster analysis of the memory CD8+ T cell development showed that high-dose infection causes a differentiation pathway that progresses faster throughout the life span of the host, suggesting a virus-host balance that is influenced by aging and infectious dose.

Importantly, short-term MCMV infection in adult mice is not disadvantageous for heterologous superinfection with lymphocytic choriomeningitis virus (LCMV). However, following long-term CMV infection the strength of the CD8+ T cell immunity to LCMV superinfection was affected by the initial CMV infectious dose, wherein a high infectious dose was found to be a prerequisite for impaired heterologous immunity. Altogether our results underscore the importance of stratification based on the size and differentiation of the CMV-specific memory T cell pools for the impact on immune senescence, and indicate that reduction of the latent/lytic viral load can be beneficial to diminish CMV-associated immune senescence.

Increased Sirt4 Modestly Increases Fly Lifespan

Researchers here show that increased levels of a mitochondrial sirtuin, sirt4, can modestly extend life in flies. Unfortunately, this sort of manipulation of metabolism - connected to nutrient sensing, mitochondrial activity, and calorie restriction - scales poorly as the life span of species increases. Short-lived species are comparatively sensitive to periodic lack of resources, and exhibit a sizable extension of life span in response to a lack of nutrients. This improves their prospects for current survival and then later reproduction when nutrients are once more available. Longer-lived species - such as our own - have for much of their evolutionary history enjoyed life spans far longer than any common period of famine, however. Thus we have a much smaller response to periods of reduced dietary nutrients, at least when considered in terms of additional healthy life, even though short-term measures of improved health are somewhat similar to those found in short-lived species.

"We show that Sirt4 is responsible for regulating both lifespan and metabolism in an organism, and specifically that it coordinates the metabolic response to fasting. We also demonstrate that overexpressing the gene for Sirt4 can extend lifespan of the fly." The results suggest that boosting Sirt4 activity may be an important avenue for treating age-related metabolic decline and disorders, such as diabetes and obesity, and promoting a healthy lifespan.

In the study, flies modified to produce extra Sirt4 saw their healthy lifespans extended by 20 percent. Removing the ability of flies to produce Sirt4 cut their healthy lives by 20 percent. Also, without Sirt4 in their cells, flies when removed from food died rapidly, even when nutrients and fats were still present in their bodies. Sirt4 belongs to a class of proteins, called sirtuins, known to regulate aspects of longevity, metabolism, genome stability, diabetes and neurodegeneration. Sirt4 is found in mitochondria, which are cellular structures where respiration and energy production take place.

Human cells contain seven different sirtuins, including three mitochondrial sirtuins, Sirt3, Sirt4 and Sirt5. Fruit fly cells contain just one mitochondrial sirtuin, Sirt 4. Increasing or decreasing expression of Sirt4 in living flies allowed the researchers to discover what function Sirt4 played in the insects - and possibly in humans. "We show for the first time that increasing the activity of a mitochondrial sirtuin can extend lifespan. No previous research has found that increasing the activity of a mitochondrial sirtuin such as Sirt4 extends the healthy lifespan of a living organism."

The study also shows Sirt4 may be a gene responsible for the metabolic action of fasting, particularly the gene vital to regulating when an organism switches from carbs to fat. A creature that lacks the gene starves to death much more rapidly than normal under poor nutritional conditions. Without Sirt4, the fly cannot access many of the nutrients and stored fats when fasting. Researchers know that temporary fasting in a living organism is valuable in resetting its metabolism. Such findings gave rise to what are called "near-starvation" diets to improve health and extend lifespan. But scientists don't know how that fasting-to-reverse-aging mechanism works. Sirtuins likely play a role. "We want to understand more about the role of sirtuins and their involvement in pathways of calorie restriction."

Gbp1 Levels Fall with Age, Making Macrophages Less Helpful and More Harmful

Polarization is a categorization scheme for the cell state and behavior of the immune cells known as macrophages, which play a variety of roles in the body, ranging from the destruction of invaders and errant cells to assisting in regeneration. For the purposes of this discussion, the interesting states are M1, inflammatory and aggressive towards intruding pathogens, and M2, in which macrophages suppress inflammation and undertake other activities that aid in regeneration. Both have their roles to play, but many of the issues that arise in aged individuals are made worse by the increasing tendency of macrophages to exhibit the M1 polarization, even when it is unhelpful to do so.

While transient inflammation is a necessary part of the immune response, chronic inflammation (such as that produced by excess fat tissue or aging) is known to be disruptive to tissue maintenance and regeneration. This consideration of macrophages and inflammation is a thin slice of a much more complicated picture, but it is an important slice. While it is true that many other changes also take place in the aged immune system, here at least, researchers appear to have identified a regulatory protein that produces many of the problems exhibited by macrophages in older individuals. It will be interesting to see where the connections lead to from here, towards specific underlying forms of cell and tissue damage that cause aging. Note that the paper is as much focused on obesity as aging, but all of the relevant mechanisms examined appear in both circumstances.

Adipose tissue inflammation is a hallmark characteristic of obesity. Macrophages that infiltrate into adipose tissue and polarize to pro-inflammatory phenotype play a key role in obesity-associated adipose tissue inflammation and insulin resistance. Mechanistically, macrophages activated with the elevation of lipopolysaccharide (LPS) and IFNγ in obesity acquire an inflammatory M1 phenotype, characterized by increased production of pro-inflammatory cytokines and reactive oxygen species (ROS). These cytokines and ROS target adipocytes to further exacerbate adipose tissue inflammation and dysfunction.

Guanylate binding protein 1 (Gbp1) is a GTPase critical for innate immunity. This has been attributed to the role of Gbp1 in transporting autophagic machinery to the pathogen containing vacuoles (PCVs). Gbp1 expression can be largely induced by IFNγ in macrophages. Most previous studies primarily focused on the role of Gbp1 in regulating innate immunity of macrophages to defend against pathogen infections. Little is known about the involvement of Gbp1 in regulating polarization, metabolic programing, and cellular aging of macrophages.

In this study, we tested the hypothesis that Gbp1 plays a role in regulating immunometabolism and senescence of macrophages. We found that Gbp1 was mainly expressed in macrophages, but not adipocytes in response to IFNγ/LPS stimulation; Gbp1 expression was significantly decreased in inguinal white adipose tissue (iWAT) of high-fat diet (HFD)-fed and aged mice. We also observed that downregulation of Gbp1 in macrophages resulted in M1 polarization and impairment of mitochondrial respiratory function possibly via disrupting mitophagy activity. Moreover, macrophages with downregulated Gbp1 displayed dampened glycolysis and exhibited senescence-associated secretory phenotype (SASP). These observations suggest that Gbp1 may play an important role in protecting against mitochondrial dysfunction and preserving immune function of macrophages during aging.

Thoughts on Mechanisms Linking Body Temperature and Aging

A fair number of papers have been published on various aspects of the link between body temperature and pace of aging. Calorie restriction in mammals both slows aging and lowers body temperature, for example. Mice with lower body temperatures due to altered temperature regulation mechanisms in the hypothalamus live a little longer. Body temperature tends to fall with advancing age in mammals, and some unusually long-lived mammals stand out for having particularly low body temperatures. When it comes to looking at the mechanisms involved in these relationships, the cellular biochemistry is very complex, and most of the relevant research has been carried out in flies and nematode worms rather than in mammals - though noted here, researchers are working their way up to the identification of interesting mechanisms in mice.

In 1916, researchers demonstrated that lower temperatures could dramatically extend the lifespan of the fruit fly, Drosophila. Other poikilothermic animals, whose internal temperature varies considerably, including C. elegans, also present increased lifespan upon modest temperature reduction. Additionally, lowering the core body temperature of homeothermic animals, such as mice, also increases lifespan, highlighting a general role of temperature reduction in lifespan extension in both poikilotherms and homeotherms. Reduction in core body temperature has been proposed to mediate the longevity benefits of dietary restriction. Conversely, raising the culturing temperature (e.g., to 25°C) greatly shortens nematode lifespan.

How is the cold-dependent lifespan extension mediated? One prominent model assumes that lowering the body temperature would reduce the rate of chemical reactions, thereby leading to a slower pace of living. This model suggests that the extended lifespan observed at low temperatures is simply a passive thermodynamic process. However, a more attractive hypothesis suggests that specific genetic programs might be engaged to actively promote longevity at cold temperatures, as observed upon dietary restriction or other paradigms.

Researchers reasoned that a cold sensor of the TRP channel family might be recruited in this process. The best-known mammalian cold sensors are TRPA1 and TRPM8; however, TRPM8 does not have a C. elegans homolog, thus ruling this receptor out of the candidate-based approach. But, TRPA1 has one ortholog in C. elegans referred to as TRPA-1, which becomes active under 20°C and therefore constitutes an attractive candidate to mediate the longevity extension observed under cold temperature.

Three temperatures (15°C, 20°C, and 25°C) are common laboratory conditions for culturing worms. If TRPA-1 is involved in promoting longevity at low temperatures, one would expect that mutant worms lacking TRPA-1 should have a shorter lifespan at 15°C and 20°C than wild-type worms, but not at 25°C. This is because this cold-sensitive channel is expected to be functional at 15°C and 20°C but remains closed at 25°C. Consistent with this prediction, trpa-1 null mutant worms showed a significantly shorter lifespan than wild-type worms at 15°C and 20°C but not 25°C. Similarly, transgenic expression of TRPA-1 under its own promoter increased lifespan at 15°C and 20°C but not at 25°C.

The ability to affect aging by manipulation of TRP channels in invertebrate models such as C. elegans provides evidence for evolutionary conservation and argues for the investigation of homologous and analogous circuits in mammalian models. Recently, evidence of the conserved function of chemosensory neurons in the regulation of longevity has been provided through the study of the capsaicin receptor TRPV1.

Impairment of TRPV1 sensory receptors is sufficient to extend mouse lifespan and improve many aspects of health in aging mice. Under normal fed ad libitum conditions, the TRPV1 mutation is not sex specific in its effects: longevity in both genders was extended to a similar extent, with 11.9% increase in male TRPV1 mutants and 15.9% increase in median female lifespan compared to wild-type controls. The longevity increase observed in these animals is not due to previously established mouse longevity paradigms such as reduced growth hormone (GH) and/or insulin growth factor (IGF-1) signaling. TRPV1 mutants show no growth delay and do not differ in body composition compared to control animals. TRPV1 mutant mice also do not present core body temperature differences with controls, arguing that their long lifespan is not due to a dietary restriction mimetic mechanism. How can a mutation in a sensory TRPV result in increased lifespan? TRPV1 mutation results in enhanced insulin secretion with age and a youthful metabolic profile that leads to increased lifespan in mice.

Yes, Of Course it is the Case that Life Expectancy at Birth Grew More Slowly in the Second Half of the 20th Century

To my eyes, the researchers here hold a few somewhat strange views of historical life expectancy data and its meaning, mixed in with the sensible thoughts, not least of which is their expectation of a ceiling or maximum to life span to exist. A great transition in trends for life expectancy at birth took place somewhere in the midst of the 20th century. In the early decades of the century, medical science made enormous inroads in the control of infectious disease, and then through to the middle of the century implementations of those advances fell in cost and spread out to less wealthy regions of the world. Infectious disease kills people of all ages, and thus large gains in life expectancy at birth can be achieved by cutting down mortality, especially in childhood. By the latter half of the century, the more tractable problems related to infectious disease were dealt with and solutions implemented to at least some degree for much of the world's population. Subsequent gains in life expectancy then had to emerge from tackling age-related diseases or the other, harder remainder of infectious disease.

To date, age-related disease has proven itself to be far less tractable a problem. As Aubrey de Grey puts it, the research community essentially took the same high level strategies that succeeded in achieving control over most infectious disease and tried to apply them to age-related disease. That simply won't work - these are two very different situations with very different causes, and which require very different solutions. The result has been marginal, expensive treatments that take a long time to produce, and thus progress towards increased life expectancy at birth has slowed. Firstly, the paradigm must change, towards something more like the SENS vision for rejuvenation through repair of the cell and tissue damage that causes aging. Secondly, life expectancy at birth is not a good metric for assessing progress towards the control of aging. Something more like remaining life expectancy at 60 is the number to pay attention to.

Increases in human life expectancy have slowed dramatically across the world since 1950, according to a new study. Although a "ceiling effect" is expected as average lifespan approaches its biological limit, the study found that the trend towards slower gains - and even declines - in lifespan is worst among low-lifespan countries. "This is not about us hitting the ceiling; the slowdown has been sharpest in countries that have the most life expectancy to gain. It's a rebuke to the idea that you can fix global health just by inventing more stuff. New health technology has been essential to making strides in life expectancy, of course, but our predecessors in the 1950s were making faster progress with the basics of soap, sanitation and public health."

Researchers examined life expectancy data for 139 countries and for each one calculated the "decadal" life expectancy gain - the gain from a given year to a decade later - during the period 1950-2009. The analysis revealed that for the total sample, the mean decadal gain started at an impressive 9.7 years during the 1950s but fell more or less steadily to just 1.9 years during the 2000s. The study did not break down data by country or region. The researchers stratified the countries in the sample by their life expectancies, and found that the highest lifespan countries, with life expectancies at birth of at least 71 years, declined from a mean decadal gain of 4.8 years in the 1950s to 2.4 years in 2000-2010. That result was unsurprising, given that life expectancies in these countries are approaching the maximum lifespan of 71-83 years.

However, the researchers found an even steeper decline in countries in the lowest stratum of lifespan, with life expectancies under 51 years. For countries in this category the mean decadal change in life expectancy dropped continuously from a promising gain of 7.4 years in the 1950s to a worrisome loss of 6.8 years in the 2000s. In other words, the low-lifespan countries on average went from experiencing big gains to sharp declines in life expectancy. The HIV/AIDS pandemic, which generally hit hardest in low-lifespan countries, is a factor in this trend but doesn't fully explain it. "The slowdown in life expectancy gains started before AIDS hit in the 1980s and 90s and occurred even in regions that did not have big problems with this disease." He suspects that an important driver of the overall trend is a widespread failure of governance. "Nowadays, the countries with persistently low life expectancy are countries that generally are fragile states."

Rapamycin Does Not Interact Favorably with Growth Hormone Receptor Knockout

The scientific community is, on the whole, very focused on exploring the effects and understanding the mechanisms of single interventions. Studies that investigate potential synergies between two or more interventions are comparatively rare. This need not be the case; it seems to be a cultural thing, a product of many various influences on funding, planning, and development. There are numerous well-established methods of slowing aging in mice, and it would be interesting to learn how they interact, whether they stack or not, even though these are largely not useful roads to greatly enhanced human longevity. Accordingly, here is one of the rare studies to examine the combined effect on life span of two interventions at once. In this case it is found that they work against one another, which at least has the potential to extend our understanding of the biochemistry of both.

Mechanistic target of rapamycin (mTOR) plays central roles in growth, metabolism, and aging. It acts via two distinct complexes: mTORC1 and mTORC2, defined by Raptor and Rictor, respectively. Rapamycin, an inhibitor of mTOR, inhibits mTORC1, and longer rapamycin treatment also inhibits mTORC2. Rapamycin was the first drug shown to extend longevity in a mammal. The effects of rapamycin on longevity were accounted for by mTORC1 inhibition, whereas information on mTORC2 is generally lacking. However, it seems that many of the negative adverse effects of rapamycin treatment are mediated by inhibition of mTORC2.

Rictor has positive effects on a variety of functions involved in whole-body homeostasis. Although at this time, the role of mTORC2 in the regulation of longevity is uncertain, several lines of evidence imply that mTORC2 may have opposite effects on aging compared with mTORC1. For instance, Rictor loss-of-function mutants in Caenorhabditis elegans had decreased life spans by 24-43% on a standard diet. Interestingly, transcriptional down-regulation of mTORC1 and transcriptional up-regulation of mTORC2 was reported to be associated with human longevity. It is vital to understand how mTORC2 regulates aging in a mammal.

mTORC2 is regulated by growth hormone (GH)-dependent growth factors. GH is essential for growth and metabolism and is involved in the control of aging. It binds and signals through GH receptor (GHR). Therefore, deletion of GHR eliminates GH signaling and its biological functions. GHR-KO (GHR knockout) mice have been a valuable tool to study GH functions, including its relationship to longevity. GHR-KO mice are dwarf, extremely insulin sensitive, and have their life span extended up to 40%. Importantly, compared with their normal littermates, GHR-KO and several other long-lived mice have decreased mTORC1 and increased mTORC2 signaling, which may play a role in their extended longevity. Therefore, we decided to examine how prolonged rapamycin treatment alters mTORC1 and mTORC2 signaling in GHR-KO mice.

In long-lived GHR-KO mice, prolonged rapamycin treatment did not further extend, but unexpectedly shortened, life span. One possible reason could be that prolonged rapamycin treatment further decreases the already low levels of mTORC1 signaling in these animals, which could adversely affect the benefits of mTORC1 inhibition. However, mTORC1 signaling was not further reduced in three key metabolic tissues of GHR-KO mice with prolonged rapamycin treatment compared with control GHR-KO mice. We cannot explain why prolonged rapamycin treatment did not further decrease mTORC1 signaling in these animals, and also cannot rule out the possibility that mTORC1 signaling may have been further reduced in other tissues.

In contrast, a significant reduction of mTORC2 signaling was evident in each of the examined tissues of GHR-KO mice treated with rapamycin. Decreased mTORC2 signaling and impaired whole-body homeostasis (which could result from reduced mTORC2 signaling) in rapamycin-treated GHR-KO mice might have contributed to the effect of prolonged rapamycin treatment on the life span of GHR-KO mice. Thus, our data indicated that mTORC2 may play a beneficial role in longevity via improving or maintaining whole-body homeostasis. Based on our data and data from previous studies, we propose the following concept: if whole-body homeostasis is impaired (which was associated with the significant reduction of mTORC2 in our study), life span could be shortened, and if mTORC2 signaling is unaltered or enhanced, inhibition of mTORC1 will lead to extension of life span. The effects of altered mTOR signaling on longevity would thus reflect a balance between inhibition of mTORC1 and enhancement, or maintenance, of mTORC2.

Towards Therapies Based on Klotho

Klotho is one of the few definitively longevity-associated genes. The protein it produces is associated with a range of important processes, though its roles are far from fully understood. Evidence exists for increased klotho to improve stem cell function, enhance cognitive function and increase synaptic plasticity in older animals, though whether or not this extends to humans is a question yet to be resolved. We might take the studies showing correlations between klotho and cognition in aged human patients as a positive sign, however. As this article notes, research groups are presently working on therapies based on delivery or otherwise enhanced levels of klotho. Given the usual relationship between degree of life extension observed in mice (large) versus humans (small) for therapies of this nature, this is probably better thought of as a potential treatment for age-related neurodegeneration, or a modest enhancement for brain function at all ages, rather than a way to extend life significantly.

Neuroscientists are taking an innovative approach to battling neurodegenerative diseases like Alzheimer's disease and dementia. Rather than trying to understand the specific mechanisms that cause each disease, they took a step back and asked, "What do all these conditions have in common?" The answer: old age. Over time, something happens to our cells and organs, and in the past three decades scientists have begun to unravel exactly what that something is - and the cellular mechanisms our bodies use to fight it.

"Aging is the biggest risk factor for cognitive problems, and cognitive problems are one of the biggest biomedical challenges that we face. Why don't we just block aging?" Blocking aging is easier said than done, but researchers jumped head first into the problem by studying a protein called klotho. The researchers who named the protein found that the amount of klotho produced by mice could affect how long the rodents lived. Other researchers later discovered that humans who naturally have more klotho tend to live longer. Living longer is one thing, but the researchers wanted to know if klotho could help our brains stay healthier and more resilient to cognitive problems. Could klotho levels predict how quickly subjects solved a variety of puzzles that test cognition? In both humans and mice, they found the same result: more klotho meant better cognitive function. To bring this boost in brain health to everyone, and not just the 20 percent of people who happen to have naturally high klotho, researchers are testing the protein's potential as a therapeutic.

The protein can exist in two forms: the first is anchored to the cell membranes of your organs, mostly your brain and kidneys; and the second occurs when the protein is cut loose from its anchor and freed to float around the bloodstream. Researchers found that by simply injecting this floating form into mice, they could re-create the cognitive boost found by genetically increasing klotho. "We found that those mice that had been treated, within four hours had better brain function. This worked in young mice, old mice, and mice that had a condition similar to Alzheimer's. Next, researchers will try to understand how klotho acts on the brain without crossing the blood-brain barrier. And ultimately, could klotho become a therapy for humans to improve brain health and protect against aging and disease? "For humans, the end game really is: how can we increase our healthspan? And that may go hand in hand with an increase in life span, because the things that help us to live longer are also the things that help us to live better."

Where Next for Cellular Reprogramming and Regenerative Medicine?

Over the past decade researchers have gained ever more expertise in reprogramming cells from one type to another. The most useful form of reprogramming devised so far is the change from normal differentiated somatic cell, fixed in its role, to pluripotent stem cell, capable of generating any type of cell given the right instructions. Surprising recent developments in this line of research include (a) evidence that performing this transformation in a living animal is beneficial rather than cancerous, producing effects similar to those resulting from a stem cell transplant, and (b) that reprogramming cells to pluripotency erases some of the markers of age in cells from old tissues.

This repair is thought to be much the same process as takes place in early embryonic development: the mechanism by which old parents can produce young children, or perhaps conceptually similar to the constant, aggressive repair and regeneration that takes place in the immortal hydra. What can be done with this knowledge? Can portions of these mechanisms be split off from the whole, understood, tamed, and selectively applied? Will that replace the current paradigm for regenerative medicine in the near future? Some people are thinking along these lines, as illustrated by this interview with a researcher in the field.

What impact will your work have on aging research?

I'm studying whether we can separate the process of functional reprogramming of cells from the process of aging reprogramming of cells. Typically these two processes happen at the same time. My hypothesis is that we can induce cellular rejuvenation without changing the function of the cells. If we can manage to do this, we could start thinking about a way to stall aging.

What is the difference between functional and aging reprogramming?

The function of a skin cell is to express certain proteins, keratins for example that protect the skin. The function of a liver cell is to metabolize. Those are cell-specific functions. Reprogramming that function means that you no longer have a liver cell. You now have another cell, which has a totally different function. Age, on the other hand, is just the degree of usefulness of that cell, and it's mostly an epigenetic process. A young keratinocyte cell is younger than an older keratinocyte but it is still a keratinocyte. The amazing thing is that if you take an aged cell that is fully committed to a certain function, and you transplant its nucleus into an immature egg cell called an oocyte, then you revert its function to a pluripotent, embryonic one, which means it can become any other cell of the body-and you also revert the age of that cell to the youngest age possible. It's mind-blowing to me.

How close are we to using pluripotency induction in therapies?

The production of induced pluripotent stem (iPS) cells in mice was described in 2006, and in humans in 2007, so it's been already 10 or 11 years. The first clinical trials using iPS cells are just about to get to early phase I and phase II. There has been a lot of hope and promise but it's been a little slow. The reason being that when it comes to clinical applications, you have to consider a number of complications. You need to know how to make the cells very efficiently, and then they need to be safe. There will be more clinical trials coming up based off iPSs. For example, I am collaborating with an iPS-based platform for the cure of a skin disease called epidermolysis bullosa. We're trying to move this to the pre-clinical stage over the next few years, and then if we pass that, we will potentially start moving into a phase I clinical trial. Things are moving forward pretty fast now.

Are germ cells immune to aging?

Yes and no. They definitely do age, but not to the same extent as other cell types. In males, spermatogenesis continues all the way from puberty to old life. If you take a 90-year-old man, there are still germ cells and spermatogonial stem cells. They do age, because it's clear that the sperm of an older man is different from the sperm of a younger man, but they do not age as heavily as other cells. This is fascinating because we do not understand the process. Female cells do age, and the consensus is that there are no germ stem cells in the ovary so these cells lack a molecular program to stay young. But once you put together an egg and a sperm, then there is an aging erasure mechanism, which is embryonic-specific, that we also do not understand.

Why are you interested in separating aging reprogramming from functional reprogramming?

The experiments of somatic cell nuclear transfer and iPS cell derivation clearly indicate that both functional and aging reprogramming can be achieved. However, these technologies are very inefficient and cannot be used as whole-body anti-aging measures because the process of reprogramming to an embryonic stage can lead to tumorigenic cells. Instead, if we could separate the two types of reprogramming and achieve only reprogramming of age without touching the function of a cell, then in principle we could apply reprogramming in vivo to every single cell in the body and rejuvenate them. This could be a paradigm shift in the way we approach aging.

An Impressive Performance in Clearing Cancer from Mice via Immunotherapy

Immunotherapy is a cut above chemotherapy and radiotherapy: at its best, it is significantly more effective and significantly less harmful to the patient. It has still required years, a great deal of funding, and many failures for those best approaches to arise. Nonetheless, the report here is a cheering example for the sizable fraction of us expected to suffer cancer at some point in the years ahead if the condition is not soon brought under medical control. This immunotherapy appears highly effective, and just importantly, adaptable to many types of cancer. This potential for broad application is the most important aspect of any potential new cancer therapy. There are hundreds of subtypes of cancer, and the research community cannot make acceptably rapid progress by dealing with them one at a time - too many years and too much funding has gone to that type of strategy in the past. The only viable way forward towards the control of cancer in our lifetime is the production of very general anti-cancer technologies, those that are effective and easily, quickly, and cheaply adapted to each type of cancer.

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases. The approach works for many different types of cancers, including those that arise spontaneously. The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient's immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides - from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times. Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

The new method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are "prescreened" by the body to recognize only cancer-specific proteins. Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors. "This is a very targeted approach. Only the tumor that shares the protein targets displayed by the treated site is affected. We're attacking specific targets without having to identify exactly what proteins the T cells are recognizing."


Hi Josh,

I want really to say thanks for your weekly work and especially for the latest list with the supplements.
I take also a lot of that stuff. It is always good to see that other
people do the same.
Best wishes Mike

Posted by: Mikel at February 11th, 2018 7:28 AM

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