The Use of Stem Cell Therapies to Treat Osteoarthritis

Today I'll point out a review paper that covers a few approaches to stem cell therapy in the context of treating osteoarthritis, a degenerative condition of the joints. Arguably the most demonstrably successful branch of stem cell medicine today is that focused on treating the issues that arise in aging joints: deterioration of tissues, wearing of bone and cartilage, and associated inflammation, pain, and loss of function. The methodologies used for mesenchymal stem cell transplants, developed over the past fifteen to twenty years, today have a good expectation of delivering noticeable improvement to patients. A short turnaround to improvement that is self-evident to the patient is an important component for success in medicine. Therapies that deliver only statistical improvements to function and risk of disease without rapid and obvious physiological improvement from the perspective of the patient - and this category still includes many stem cell therapies for internal organ damage at this point - are a much harder sell at all levels of development.

Stem cell activity declines with age, a reaction to growing levels of cell and tissue damage. This decline is thought to trade off risk of death by cancer on the one hand, the result of damaged cells undertaking more activity, with risk of death due to loss of tissue function on the other hand, the result of stem cells becoming less active and thus delivering fewer replacement cells to the tissues they support. Restoring stem cell populations to their youthful undamaged and active state is a necessary component in any future rejuvenation toolkit. Present day stem cell therapies do not achieve this goal, however. They appear to work largely by altering the local signaling environment for a short period of time, putting existing cells back to work, spurring greater regeneration, and reducing inflammation. The transplanted cells in many cases live only a short time. Most stem cell therapies available today should be viewed as a burst of rebuilding, but rebuilding that uses damaged tools and damaged materials. Nonetheless, even though this is compensation, not rejuvenation, it can result in significantly better patient outcomes than the other presently available options.

Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review

Osteoarthritis (OA) is a major cause of disability and chronic pain, characterized by progressive and irreversible cartilage degeneration. The capacity of articular cartilage to repair is inherently poor, with the relative avascularity of cartilage, and hence lack of systemic regulation, likely leading to an ineffective healing and reparative response. With advances in modern medicine improving the prevention, diagnosis and treatment of many diseases that were once life-threatening, the population is now living longer. This increased life expectancy has led to an increased burden of degenerative conditions including osteoarthritis. Current medical treatment strategies for OA are aimed at pain reduction and symptom control rather than disease modification. These pharmaceutical treatments are limited and can have unwanted side effects. The health and economical impact of OA has seen it become an international public health priority and has led to the active exploration and research of alternative regenerative and joint preservation therapies including mesenchymal stem cells.

Whilst both mechanical, genetic and other factors influence development of OA, the primary risk factor is age. Components of the cartilage extracellular matrix (ECM) including type II collagen and proteoglycans undergo age-related structural changes, leading to likely alteration in the biomechanical properties of the ECM. Advanced glycosylation end products also accumulate within cartilage, leading to increased cross-linking and altered biomechanical properties. These changes lead to a loss in the ability of cartilage to adapt to mechanical stress/load. Chondrocytes within the cartilage matrix also exhibit age related changes. It has been proposed that reactive oxygen species (free radicals) induced by mechanical or biological stressors may lead to cell senescence. Cell senescence is accompanied by reduced growth factor response and production, coupled with an observed upregulation of inflammatory cytokine expression. Evidently there are a host of enzymatic compounds that are involved in the disruption of the collagen matrix leading to the degradative process of OA.

Interestingly, evidence indicates that osteoarthritis is associated with a depleted local population of stromal mesenchymal stem cells (MSCs), and those that exist exhibit reduced proliferative and differentiation capacity. The depletion and functional alteration/down regulation of MSC populations with reduced differentiation capacity has also been postulated as a cause for progressive degenerative OA. Despite these findings, it has been noted that there exists MSCs with chondrogenic differentiation potential in patients with OA, irrespective of age or the etiology of disease.

MSCs, due to ease of harvest and isolation with minimal donor site morbidity, coupled with an ability to expand into chondrocytes, have meant that they have been actively explored in regards to tissue engineering and repair. Preclinical trials using techniques similar to autologous harvesting of cartilage from a non-weight bearing area, but substituting chondrocytes with MSCs, have shown positive results with formation of tissue with histological properties consistent with hyaline cartilage and a high type II collagen presence. Others have successfully transplanted isolated MSCs - seeded onto a type I collagen network - to an area of chondral defect, resulting in successful filling of the defect. Later biopsy at two years indicated hyaline like cartilage with type II collagen on histological evaluation.

Recognizing the limitation of biological scaffolds in the treatment of OA - where there exists more diffuse cartilage loss rather than an isolated cartilage lesion - other researchers have sought to assess the effect of intra-articular MSC injections. Preclinical trials have successfully indicated the benefit of MSC intra-articular injections on improvement in function, though results have been inconsistent on cartilage restoration. Some studies, whilst indicating significant pain and functional improvement, have not seen any observable difference in disease progression against controls, whilst others have successfully shown disease modification. Similarly to preclinical results, clinical trials using injectable MSC techniques have reproducibly shown pain and function improvements, though observation of disease modification has been less consistent. Most recently, Phase I and II trials using expanded adipose derived MSCs in the treatment of OA have shown MRI evidence of cartilage regrowth. Following a single intra-articular injection of 100 million MSCs, radiological (MRI) follow-up at 6 months showed increased cartilage volume and histological assessment confirmed hyaline-like cartilage regeneration with the presence of type II collagen.

Despite MSCs being commonly associated with regenerative medicine, and level IV evidence of chondral regrowth and disease modification, there is a paucity of well-controlled trials assessing structural outcome. The reproducible pain and functional improvement seen with MSC injectable therapies, raises the question of whether the biological mechanism of action may be a strong anti-inflammatory effect - including on neurogenic inflammation - rather than regeneration. Further, the observed disease modification in studies that use combination therapy suggests that the efficacy of MSC therapies may be influenced by additional agents including platelet concentrates and hyaluronic acid - though this creates a further layer of confusion regarding cause and effect. Nonetheless, MSC based cell therapies offer an exciting possibility in the treatment of OA and importantly show promise in disease modification, with potential inhibition of progression and recent evidence of reversal of this degenerative process.

Reviewing What is Known of FGF23 and Klotho Signaling in Aging

In past years researchers have demonstrated in animal studies that reduced levels of klotho can shorten life span while increased levels modestly extend life span. The underlying mechanisms are complex and not fully understood. As is also the case for other longevity-related proteins, altering levels in circulation through gene therapy or other methods changes many aspects of cellular metabolism. Unraveling this complexity is a slow and expensive process. One small part of the bigger picture in this case is the relationship between klotho and fibroblast growth factor 23 (FGF23). The review paper below examines what is known on this topic:

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption and vitamin D hormone production in the kidney. Klotho was originally discovered as an anti-aging factor, but the functional role of Klotho is still a controversial issue. Three major functions have been proposed, a hormonal function of soluble Klotho, an enzymatic function as glycosidase, and the function as an obligatory co-receptor for FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23 and Klotho signaling in the kidney, in the parathyroid gland, in the cardiovascular system, in bone, and in the central nervous system.

Recent advances in the field of FGF23 and Klotho biology have revealed major new functions of FGF23 and Klotho signaling in the kidney, in the heart, in bone, in blood vessels, and in the parathyroid gland. It is now clear that FGF23 is far more than only a phosphaturic bone-derived hormone. Rather, FGF23 has emerged as a pleiotropic endocrine and auto-/paracrine factor not only involved in phosphate homeostasis, but also in calcium and sodium metabolism, in bone mineralization as well as in the development of cardiac hypertrophy. These novel findings have linked phosphate with volume homeostasis, and may have major pathophysiological implications for chronic kidney disease, cardiovascular diseases, and disorders of bone mineralization.

Link: http://dx.doi.org/10.1016/j.mce.2016.05.008

Telomere Length Suggested as the Mechanism Limiting Heart Regeneration

Evolution has left mammals with only a limited ability to regenerate heart tissue. Unlike very regenerative species such as salamanders or zebrafish, we lose most of our ability to heal the heart very early in life. Here, researchers suggest that this is keyed to reduced telomere length in heart cells, but in a way that is very different to the more familiar erosion of average telomere length that occurs over the course of aging. Here, that reduced length is a developmental process occurring in early childhood. If this work bears out, it actually sounds like a much more compelling argument for the use of telomerase therapies in medicine than those based on trying to address age-related telomere erosion, as that erosion is most likely only a marker of age-related damage, not a cause:

Researchers have discovered that the ends of heart muscle cell chromosomes rapidly erode after birth, limiting the cells' ability to proliferate and replace damaged heart tissue. Newborn babies can repair injured myocardium, but, in adults, heart attacks cause permanent damage, often leading to heart failure and death. Newborn mice can also regenerate damaged heart tissue. Their heart muscle cells, or cardiomyocytes, can proliferate and repair the heart in the first week after birth, but this regenerative capacity is lost as the mice grow older and the majority of their cardiomyocytes withdraw from the cell cycle.

Researchers wondered whether the cause of this cell cycle arrest might involve telomeres, repetitive DNA sequences that protect the ends of chromosomes. If telomeres grow too short - due, for example, to a loss of the telomere-extending telomerase enzyme - cells can mistake chromosome ends for segments of damaged DNA, leading to the activation of a checkpoint that arrests the cell cycle. The researchers therefore examined the length of telomeres in newborn mouse cardiomyocytes and found that the telomeres rapidly eroded in the first week after birth. This erosion coincided with a decrease in telomerase expression and was accompanied by the activation of the DNA damage response and a cell cycle inhibitor called p21.

Telomerase-deficient mice have shorter telomeres than wild-type animals, and, the researchers discovered, their cardiomyocytes already begin to stop proliferating one day after birth. When the researchers injured the hearts of one-day-old mice, telomerase-deficient cardiomyocytes failed to proliferate or regenerate the injured myocardium. In contrast, wild-type cardiomyocytes were able to proliferate and replace the damaged tissue. They also found that knocking out the cell cycle inhibitor p21 extended the regenerative capacity of cardiomyocytes, allowing one-week-old p21-deficient mice to repair damaged cardiac tissue much more effectively than week-old wild-type animals. Maintaining the length of cardiomyocyte telomeres might therefore boost the regenerative capacity of adult cells, improving the recovery of cardiac tissue following a heart attack. "We are now developing telomerase overexpression mouse models to see if we can extend the regenerative window."

Link: http://www.eurekalert.org/pub_releases/2016-05/rup-msl052516.php

Disruptive Change in Aging Research Arrives from the Outside

Disruption is a part of progress. All communities of research and development go through cycles in which (a) the established mainstream and its insiders become slow and ineffective, (b) outsiders become frustrated given the unrealized potential for faster progress and better outcomes, (c) some of these outsiders succeed in developing a vastly better path forward, despite being opposed at every turn by the mainstream, (d) the new path forward displaces the existing mainstream, and the outsiders become the new leaders and insiders, (e) with time, this new mainstream becomes slow and ineffective. So the cycle repeats.

In the matter of medicine, aging, and longevity, we are presently somewhere in the midst of step (c). The mainstream of ineffective, expensive approaches to the treatment of age-related conditions is ineffective and expensive because it fails to consider or address the root causes of aging. Try making any damaged machine work better and longer while not actually repairing the damage - it isn't easy. The typical approach to research is to start with the end stage disease state and work slowly and painfully backwards through a very complex dysfunctional metabolism. At the first proximate cause, stop and try to build a treatment that can manipulate the diseased metabolic state so as to make the proximate cause less onerous to the patient. Then return to tracing the disease backwards towards root causes. There are so many layers of proximate causes in most diseases that this type of approach can continue - and has continued - for decades without ever getting close to the cell and tissue damage that is the root cause of aging, and thus the root cause of all age-related disease.

This, however, is the mainstream, the default approach. It is an established culture, reinforced by regulation and tradition, and will change but little without disruption. The most important outsiders attempting to disrupt aging research in favor of effective progress towards treatment of aging are those of the small community that built and supported the Methuselah Foundation and SENS Research Foundation, pulling in philanthropic funding and gathering allies in support of a repair-based approach to the treatment of aging. The fundamental, root causes of aging are well cataloged, forms of cell and tissue damage caused by the normal operation of metabolism, so why wade through the mud of how exactly aging progresses in detail from these causes, and why start at the end and work backwards? Just fix the known causes using any of the envisaged and planned potential classes of repair therapy and see what happens. The potential for cures first, full understanding later: too many people are dying to indulge the mainstream's preferred approach.

We are far enough into this process of disruption that some outsiders have become scientists and some scientists have joined the insurrection. There are thousands of supporters of rejuvenation research, there is respectful and informed press attention, and tens of millions of dollars have been deployed to advancing this cause. The first rejuvenation therapies are under development in startup companies. We're almost at the stage where the people who at the beginning carried out the hard, thankless work of spreading new ideas, obtaining support, and kicking shins - telling the scientific community that they were going about everything the wrong way - start to be buried by the second wave. It is the fate of all pioneers to be forgotten and trodden upon by a collaboration between later newcomers, those with more resources to claim the mantle of leadership, and those of the former mainstream who decide to pretend that they agreed all along. Such is life. It is frustrating, but the important thing is not the credit, but that the job will be done, that repair-based therapies for aging will become the new mainstream on the basis of obtaining far better results than the present approaches to aging. Life and health before pride.

The article linked below struck me as exhibiting a nice mix of many of the agendas that come to the fore during the disruption of an industry, ranging from the several factions intent on burying the original disruptors to individuals with the mainstream attempting to present a slight adjustment of their methods as an alternative to the still vastly better disruptive technology. I'm not sure I agree with all of the core thesis. Some of those presented as outsiders, such as Larry Ellison and Paul Glenn, were almost immediately co-opted by the mainstream of the time. There isn't enough of a distinction made between for-profit and philanthropic funding, as the latter has been vastly more influential and important over the years in which I've been observing progress in aging research. But see what you think.

Despite the hyperbole, private funding is changing the science of aging for the better

I've been led here by Sonia Arrison, a Silicon Valley local and author of 100-Plus: How the Coming Age of Longevity Will Change Everything. Arrison has agreed to show me around her strange Californian world, populated with very wealthy, very smart dreamers, who share her certainty that a longevity revolution is on its way. We've arrived on Joon Yun's doorstep to learn how and why he, along with a small group of big power players, plan to "cure" aging and extend human health span - and possibly even human life - by decades, if not centuries. "I essentially made a wager to myself that aging is a code," Yun explains to me from across a shiny conference table. "If aging is a code, that code could be cracked and hacked. The current system in healthcare is a whack-a-mole of your symptoms until you die. It addresses the diseases of aging, but not curing the underlying process behind aging itself. The healthcare system is doing a good job of helping people live longer and stronger lives, but aging is still a terminal condition." In 2014, Yun created the Race Against Time Foundation and Palo Alto Prize, which will award $1 million to a team that can demonstrate the capacity to mitigate aging by, among other things, extending the life of a mammal by 50 percent.

Faith that science will conquer aging is common in Silicon Valley these days. The language Yun uses to explain his dream - especially the use of the word "cure" - makes traditional researchers in the field of aging cringe. But few are complaining about the interest of the big-spending Silicon Valley crowd. In recent years, public institutions like the National Institutes of Health have been slow to commit any more than a token of their overall budgets to aging research. It is the private funders with big dreams who are galvanizing the field. The Ellison Medical Foundation has spent nearly $400 million on longevity research. Oracle founder Ellison told his biographer, "Death makes me very angry." PayPal cofounder and venture capitalist Peter Thiel helped fund the SENS Research Foundation, a longevity organization co-led by British gerontologist Aubrey de Grey, who's argued we might someday halt aging and extend life indefinitely. (Arrison, Thiel's longtime friend, introduced the two).

In 2013, the founders of Google launched Calico, short for California Life Company, to research aging and associated diseases. A year later Calico teamed up with the biopharmaceutical company AbbVie, with which it plans to invest up to $1.5 billion to develop age-related therapies. "With some longer term, moonshot thinking around healthcare and biotechnology, I believe we can improve millions of lives," wrote Google cofounder Larry Page. The quest to extend longevity makes perfect sense in Silicon Valley, explains Lindy Fishburne, a longtime lieutenant of Thiel's, in her stately office in San Francisco's Presidio, a former military base that sits on a pictorial tip of the San Francisco Bay. "It's the engineering culture which says we'll build our way out of it, we'll code our way out of it, there has to be a solution. I also think it's coupled with a very unique optimism that is pervasive in Silicon Valley."

It is worth noting that all too few of the people and funding sources mentioned in the article are in fact backing the repair-based approaches to rejuvenation that are, to my eyes, the most likely to realize a future of greatly extended healthy lives, and to accomplish these gains soon enough to matter to you and I. Many of those involved are either already or on their way to being captured by the present ineffective mainstream, just like Ellison and Glenn. Nonetheless, disruption is underway, and threads of meaningful work will continue to grow. It is still early enough in this process that ordinary folk like you and I can make a mark: our philanthropy and support for the SENS Research Foundation and similar organizations in past years has produced meaningful change in the status quo, and that change is spreading.

Tinkering with Sensory Pathways as an Approach to the Development of Calorie Restriction Mimetics

Most laboratory species - such as flies, worms, mice, and other mammals - have been shown to age somewhat more slowly in response to calorie restriction; it changes near every measure of metabolism and improves near every measure of health. The effects on lifespan are much more pronounced in short-lived species than in long-lived species such as our own, but the effects on human health are still pretty impressive. It has been a few years now since researchers first found that the calorie restriction response has some dependency on sensory perception of food in species such as nematode worms and flies. This is an as yet largely unexplored avenue for the development of calorie restriction mimetic drugs that might recapture some of the benefits of eating less without the need to eat less:

Researchers have shown a new effect on aging via a small drug-like molecule that alters the perception of food in the nematode C. elegans. The researchers "tricked" the worm's metabolism into a state of caloric restriction, extending the animal's lifespan by 50 percent. The study provides a new avenue of inquiry for researchers around the world who are attempting to develop human drugs that mimic the positive effects of a Spartan diet. "This small molecule blocks the detection of food in the worm's mouth. The worm senses that its mouth is empty even when it is full of food, tricking the animal into shifting its physiology into a caloric restricted-state even when it's eating normally. Our study suggests that primary sensory pathways represent new targets for human pharmacology."

Researchers screened 30,000 synthetic, drug-like compounds in nematodes and identified several structurally related compounds that acted on mechanisms tied to caloric restriction. They found that the small molecule, NP1, impinged upon a food perception pathway by promoting glutamate signaling in the pharynx of the animal. The chemical activated a neurotransmitter-controlled food deprivation signal which altered the animal's normal metabolism into a caloric restriction state. Exploring sensory pathways as potential drug targets should be of interest to age researchers interested in mimicking caloric restriction in order to extend healthspan. The mechanisms involved in sensory pathways may be more specific than secondary pathways that detect energy levels or absorbed nutrients at the cellular level, such as the intracellular pathways mTOR and AMPK which are under study in many labs around the world. "Targeting sensory pathways may lead to a more rapid response to changing diet. Altering these higher level, specific response mechanisms may also have fewer effects on other systems in the body."

Link: http://www.eurekalert.org/pub_releases/2016-05/bifr-cwe052616.php

DNA Damage as an Important Determinant of Vascular Aging

The authors of this paper argue that stochastic mutational damage to nuclear DNA is important in the progression of vascular aging, the declining function and structural integrity of blood vessels. It is more or less the consensus hypothesis that nuclear DNA damage does broadly contribute to all facets of the aging process by causing a growing random dysregulation of cellular activity, and is not just a matter of cancer risk. There those who argue the opposite position, however, that while this is damage, outside of cancer risk nuclear DNA mutations don't create enough disarray over a normal human lifetime to matter in comparison to other forms of cell and tissue damage. As for most of the molecular damage of aging, there is a lot of room to argue over relative importance because there are few presently available ways to repair any one form of damage in isolation to see what happens. If all forms of damage could be so repaired, then the research community would certainly know how important each was, but that still lies in the future.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, responsible for killing 17.3 million persons per year. The onset of CVD is triggered by vascular endothelial alterations characterized by an impaired endothelium-dependent vasodilation, the overproduction of pro-inflammatory and prothrombotic molecules, and oxidative stress. Age is the strongest independent predictor for CVD in risk scores in middle-aged persons, and an important determinant for cardiovascular health in the population aged 65 or older. Aging is characterized by the complex interaction of cellular and molecular mechanisms that leads to a collection of functional problems. Focusing on the vasculature, such problems are closely associated with each other, and include worsened vasodilation, increased arterial stiffness and overt remodeling of the extracellular matrix, diffuse intimal thickening and a dysfunctional endothelium. The mechanisms through which age actually contributes to cardiovascular risk remain the subject of speculation.

A recently proposed alternative view on vascular aging has emerged that presents new mechanistic alternatives for understanding the process of vascular aging. In this novel paradigm, causal mechanisms for the process of aging itself, most notably genomic instability, including telomere attrition, drive the detrimental changes occurring increasingly with (biological) aging. In the present review we summarize the evidence that supports the role of genomic instability in vascular aging. In addition, we present mechanisms through which genomic instability generates the functional changes that are typical for the aging vasculature.

Nuclear DNA lesions, among which is telomere erosion, and mitochondrial DNA damage are strongly associated with several main features of vascular aging, such as diminished vasodilator capacity and increased vasoconstriction, increased blood pressure, increased vascular stiffness and atherosclerosis. Pivotal cellular biological changes involved in these pathological features comprise cellular senescence, apoptosis, autophagy, stem cell exhaustion and altered proliferative capacity of vascular cells. The role of gene mutation and of compromised transcription remains unknown. Potential mediating signaling pathways involved include components of the survival response, notably antioxidants under regulation of Nrf2 (beneficial), increased inflammatory status (detrimental) and decreased IGF-1/GH signaling (detrimental), as well as the interplay between mTOR, AMPK and NFκB, SIRT-1, and PAI-1, p53- and p21- and p16-related signaling. Proposed remedies against genomic instability-related vascular aging include PAI-1 inhibition, mTOR inhibition, dietary restriction, senolytics, PDE1 and PDE5 inhibitors and stimulators of Nrf2.

Link: http://www.mdpi.com/1422-0067/17/5/748/htm

Borrowed Immune Cells to Fight Cancer

It is an unfortunate fact of life that many promising avenues of medical research languish partially developed and unfunded. It isn't unusual to see potentially transformative medical technologies linger with little further progress for a decade or more after their first triumphant discovery. The innovative antiviral DRACO technology is one such, offering the potential of therapies for persistent infections that cannot currently be treated. Another is the use of immune cell transplants to attack cancer, presented in its initial form of granulocyte infusion therapy (GIFT) with accompanying compelling animal data at the third SENS conference in 2007, but under development for years prior to that point. Where is this approach to cancer treatment today, nearly a decade down the line? Little advanced beyond that point, I'm sorry to say. In fact so little progress has occurred and so little attention has been given to this style of cancer treatment that other researchers are now and then independently finding their way to the same place from different directions, as noted in the paper and publicity materials that are linked below.

Why does this waste of potential continue to happen over and again in the field of medical research and development? One challenge is that a life in the fairly rigid hierarchy of the sciences is typically poor preparation for the cut and thrust of bringing a new technology into the marketplace, raising funding outside the established channels of grants, and working with businesses. That is an entirely different set of skills and talents. Some scientists have those skills and talents, and you'll tend to see those people starting companies or leading laboratories. Most do not - just as there are few entrepreneurs and leaders in the general population, there are also few entrepreneurs and leaders within the scientific community. There are only so many hours in the day, time spent on one set of skills is not spent on another, and science is a demanding partner. Just because a team makes a solid advance in their field doesn't mean they are well positioned or qualified to make it a success after that point.

Another issue, important in this case, is that the combination of heavy regulation of medicine, regulatory capture, and the consequent dominance of very conservative large developers and very expensive development processes means that medicine rarely moves forward for any potential treatment in which the biochemical mechanisms cannot be explained. Ten years ago, there was no good explanation for why GIFT was so good at defeating cancer in mice. Progress within the system and the present cultural edifice of cancer research required that explanation - the idea of moving ahead based purely on great results doesn't win you support from Big Pharma, and without that support there are few organizations with deep enough pockets to move ahead through the burdensome FDA processes as they stand these days. So while there have been trials of immune infusion therapies for cancer, these were small and funded from other sources. That backing is not extensive. There have been some signs of availability in the medical tourism space, but without more of a mainstream interest in the field that is also so far anemic.

An entirely different class of problem contributing to the existence of moribund fields of research is the lack of funding and attention given to medical research in general. Very little of medical research is funded to anywhere near a reasonable level given the potential expectations for resulting benefits. To a first approximation, no-one cares about medical research and medical progress, or at least not until it is far too late to do anything about it. Research survives on the scraps and margins of philanthropy of this wealthy society. Bread and circuses before progress, and near all of the money in medicine goes towards using the technology that exists, even when there are much better alternatives within reach, just a few years of development away.

Fighting cancer with the help of someone else's immune cells

Researchers decided to test whether a "borrowed immune system" could "see" the cancer cells of the patient as aberrant. The recognition of aberrant cells is carried out by immune cells called T cells. All T cells in our body scan the surface of other cells, including cancer cells, to check whether they display any protein fragments on their surface that should not be there. Upon recognition of such foreign protein fragments, T cells kill the aberrant cells. As cancer cells harbor faulty proteins, they can also display foreign protein fragments - also known as neo-antigens - on their surface, much in the way virus-infected cells express fragments of viral proteins. To address whether the T cells of a patient react to all the foreign protein fragments on cancer cells, the research teams first mapped all possible neo-antigens on the surface of melanoma cells from three different patients. In all 3 patients, the cancer cells seemed to display a large number of different neo-antigens. But when the researchers tried to match these to the T cells derived from within the patient's tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.

Next, they tested whether the same neo-antigens could be seen by T-cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neo-antigens that had not been seen by the patients' T cells. "In a way, our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens. The receptor that is used by these donor T-cells can then be used to genetically modify the patient's own T cells so these will be able to detect the cancer cells. Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput."

Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation-derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies to broaden neoantigen specific T cell responses are therefore attractive. Here, we demonstrate that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11/57 predicted HLA-A2-binding epitopes from three patients. Many of the T cell reactivities involved epitopes that in vivo were neglected by patient autologous tumor-infiltrating lymphocytes. Finally, T cells re-directed with T cell receptors identified from donor-derived T cells efficiently recognized patient-derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such "outsourced" immune responses in cancer immunotherapy.

The Possibility of Reducing Amyloid in the Brain by Reducing it Elsewhere

This paper explores the mechanisms by which the amyloid associated with the progression of Alzheimer's disease can be cleared naturally outside the brain. It raises the possibility that finding ways to reduce amyloid outside the brain will allow existing transport and clearance mechanisms to export and remove more of the amyloid from the brain. A counter-argument to this hypothesis is that these transport and clearance mechanisms become damaged and dysfunctional with age. There are, for example, research groups examining the drainage of cerebrospinal fluid, one of the ways in which amyloid might leave the brain, who have found this fluid flow diminished in Alzheimer's patients. There is similar work on age-related declines in the mechanisms for filtration of cerebrospinal fluid that are located in the choroid plexus. It is a still open question as to the degree that these various mechanisms - and others - contribute to the overall progression of Alzheimer's disease. The best way to answer that question is to repair individual suspected causes one at a time, and see what happens as a result.

Alzheimer's disease (AD) is the most common form of dementia among the elderly. Senile plaques containing amyloid-beta protein (Aβ) in the brain are a pathological hallmark of AD and they play a pivotal role in AD pathogenesis. The steady-state level of Aβ in the brain is determined by the balance between Aβ production and its clearance. In the brain, Aβ can be cleared via microglial phagocytosis and proteolytic degradation by enzymes such as neprilysin (NEP) and insulin-degrading enzyme (IDE). Transport of Aβ from the brain into the peripheral blood has been demonstrated in both animal models and humans. There are several potential pathways for the efflux of brain Aβ into the periphery. These include transport across the blood-brain barrier (BBB) mediated by low-density lipoprotein receptor-related peptide 1 (LRP1), drainage from interstitial fluid (ISF) into cerebrospinal fluid (CSF) via perivascular or glymphatic pathways, reabsorption from CSF into the venous blood via arachnoid villi and blood-CSF barrier, or into the lymphatic system from the perivascular and perineural spaces, and possibly via meningeal lymphatic vessels.

The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected 125I labeled Aβ40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aβ derived from the brain can be cleared in the periphery. Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575389/

Arguing for More and Better Studies of the Comparative Biology of Aging

In this open access paper, the author argues for greater investigation of the fundamentals of aging in various species, for more comparisons of the biochemistry of aging between wild and laboratory populations, and for greater collaboration between some of the distinct communities within the aging research community:

Aging (senescence) is an increase in mortality risk with age due to deterioration of vital functions. Understanding the mechanisms and consequences of aging is not only an intriguing evolutionary question but also a matter of practical concern with pressing demographic and societal implications. The two aspects of aging research - fundamental understanding of why organisms age and how aging patterns in nature vary on the one hand, and an applied perspective dealing with biomedical treatments of aging on the other - have entered an exciting phase. I argue that the next steps to understand the biology of aging should combine approaches and concepts used by the two research communities.

Biogerontologists are interested in proximate mechanisms of aging, use laboratory models and focus on means of mitigating specific functional declines associated with aging. Advances in biogerontology have demonstrated that these proximate mechanisms of aging and interventions to modify lifespan are shared among species. Evolutionary biologists seek to understand why aging has evolved and how and why it varies among populations and species. Long-standing theories to explain the evolution of aging have recently been found unsatisfactory in their ability to explain many observed patterns of aging, revealing how incomplete our understanding of the evolutionary aspects of aging (and variation in aging rates within and among species) currently is. A systematic feedback between functional and evolutionary research on aging is needed to provide mutually beneficial critical insights into the biological basis of aging.

In nature, aging patterns have proven more diverse than previously assumed. The paradigm that extrinsic mortality ultimately determines evolution of aging rates has been questioned and there appears to be a mismatch between intra- and inter-specific patterns. The major challenges emerging in evolutionary ecology of aging are a lack of understanding of the complexity in functional senescence under natural conditions and unavailability of estimates of aging rates for matched populations exposed to natural and laboratory conditions. I argue that we need to reconcile laboratory and field-based approaches to better understand (1) how aging rates (baseline mortality and the rate of increase in mortality with age) vary across populations within a species, (2) how genetic and environmental variation interact to modulate individual expression of aging rates, and (3) how much intraspecific variation in lifespan is attributable to an intrinsic (i.e., nonenvironmental) component. I suggest integration of laboratory and field assays using multiple matched populations of the same species, along with measures of functional declines.

Link: http://onlinelibrary.wiley.com/doi/10.1002/ece3.2093/full

When Looking at Stem Cell Activity, Even Short-Lived Sea Urchins Appear to be Negligibly Senescent

The paper I'll share today takes a look at stem cells over the course of aging in different sea urchin species that exhibit radically different life spans, ranging from a few years to somewhere north of a century. A fair number of marine species, some urchins included, are negligibly senescent, meaning that they show few signs of degeneration or increased mortality due to intrinsic causes until very close to natural death. In some cases it has been impossible to measure life span in a random sample gathered from the ocean, as was true for lobsters until recently, and that combined with the paucity of funding for investigating the aging of sea life has meant that the research community has no good, certain data for the maximum life span of many of these species.

When looking at lower life forms that appear to be ageless or very close to ageless, such as hydra, a common theme is hyperactive, proficient, constant regeneration of all tissues. Since distinct populations of stem cells serve this purpose in hydra and higher species, both those that are negligibly senescent and those that age gracelessly, it makes sense to gain a better understanding of how stem cell biology differs between those who age and those who age less. This isn't just longer lives versus shorter lives, but perhaps more importantly how much of an age-related decline occurs across the life span. There are also other compelling reasons for such an investigation, such as the differences between salamanders, capable of regrowing limbs and organs, and mammals, who cannot. That may be somewhat orthogonal to the question of how stem cell biology affects aging, since it is debatable as whether or not salamanders are negligibly senescent. This isn't a classification with a clear dividing line, and many species are happy to occupy the large grey area. Still, that is a problem solved by gathering more data, and by gaining more knowledge - and thus at root by funding more research.

In our species, and most others of interest, stem cell activity declines with age. The conventional wisdom, not unchallenged, is that this serves to give us additional time free from cancer at the expense of a loss of tissue maintenance, producing growing frailty and increasing organ failure. Damaged cells undertaking activity raise the risk of cancer. If those cells instead remain quiescent, there is less of a risk. In the view of aging as an accumulation of cell and tissue damage, stem cells shut down in response to rising levels of damage. But how does this all work in negligibly senescent species, and - as ever - how might the research community port over some of those benefits into our biochemistry in a cost-effective manner? For my money, I'd guess that this line of development is destined to be lengthy and expensive, but that is the way of most research. The better path as I see it is to repair the damage that causes stem cells to react by retreating from their work, and to replace those stem cell populations wholesale where the cells have themselves become damaged. The present stem cell industry is a good first step on that road, but there is much more yet to be done to reach the desired endpoint.

Is aging inevitable? Not necessarily for sea urchins

Sea urchins are remarkable organisms. They can quickly regrow damaged spines and feet. Some species also live to extraordinary old ages and - even more remarkably - do so with no signs of poor health, such as a decline in regenerative capacity or an increase in age-related mortality. Researchers study the regenerative capacity of sea urchins in hopes that a deeper understanding of the process of regeneration, which governs the regeneration of aging tissues as well as lost or damaged body parts, will lead to a deeper understanding of the aging process in humans, with whom sea urchins share a close genetic relationship.

Researchers studied regenerative capacity in three species of sea urchins with long, intermediate and short life expectancies: the red sea urchin, Mesocentrotus franciscanus, one of the world's longest-lived organisms with a life expectancy of more than 100 years; the purple sea urchin, Strongylocentrotus purpuratus, with a life expectancy of more than 50 years; and the variegated sea urchin, Lytechinus variegatus, with a life expectancy of only four years. The scientists hypothesized that the regenerative capacity of the species with shorter life expectancies would decline as they aged. Much to their surprise, however, they found that regenerative capacity was not affected by age: as with the very long-lived sea urchin, the regenerative capacity of the species with a shorter life expectancy did not decline with age. "We wanted to find out why the species with short and intermediate life expectancies aged and the long-lived species didn't. But what we found is that aging is not inevitable: sea urchins don't appear to age, even when they are short-lived. Because these findings were unexpected in light of the prevailing theories about the evolution of aging, we may have to rethink theories on why aging occurs."

Maintenance of somatic tissue regeneration with age in short- and long-lived species of sea urchins

Sea urchins exhibit continued growth and reproduction throughout their lives and yet different species are reported to have vastly different life expectancies in the wild. The proper balance of cell division and cell death is important for life-long growth and homeostasis and maintaining this balance with age would be essential to achieve negligible senescence, whereas failure to maintain this balance would promote aging and shortened lifespan. In this study, cell proliferation was measured using in vivo incorporation of 5-bromo-2′-deoxyuridine (BrdU).

It was determined that there was a low level of BrdU incorporation and apoptosis in the internal tissues of three species of sea urchins with different lifespans, regardless of age. The low levels of cell proliferation are consistent with the low metabolic rates that have been reported for sea urchins, and suggest that unlike Hydra, sea urchins do not avoid senescence by continually replenishing tissues at a high rate. As expected for animals that grow indeterminately, there were higher levels of cell proliferation compared to apoptosis in the tissues. The low levels of apoptosis in the tissues of young and old animals are consistent with low levels of cellular damage that does not increase with age. Interestingly, in L. variegatus and S. purpuratus, which have a ~ 10-fold difference in lifespan, there were few differences in the amount of cell proliferation and apoptosis in tissues compared within age categories.

To determine whether regenerative potential was maintained with age in sea urchins, the regrowth of amputated spines and tube feet was measured in L. variegatus and S. purpuratus. The data demonstrate that the regenerative potential of both types of appendages was maintained with age in these sea urchin species. A prediction from the evolutionary theories of aging is that level of extrinsic mortality influences the rate of aging, such that high levels of extrinsic mortality would be associated with tissue decline once an organism reaches reproductive maturity and survivorship in the wild becomes increasingly unlikely. L. variegatus is predicted to have a much lower annual survival rate than S. purpuratus and M. franciscanus and an estimated lifespan in the wild of about 4 years, and yet the results did not show evidence of decline in regenerative capacity in larger/older animals. It is possible that L. variegatus have the potential to live much longer than has been reported in the wild (and hence that the animals used in this study were not approaching their maximum lifespan potential), or that longevity in these animals is not limited by investment in (or capacity for) maintenance and repair of damaged tissues.

The lack of age-related differences in the maintenance of tissue homeostasis and regenerative potential in sea urchin species with different lifespans were unexpected in light of current evolutionary theories of aging, and further study is required to understand the factors underlying the short lifespan of L. variegatus in particular.

Single Gene Mutation Reduces Cardiovascular Disease Risk in Humans

Researchers have uncovered evidence for a rare natural genetic mutation in our species that lowers blood cholesterol and thus reduces risk of some forms of cardiovascular disease. Given the results reported in the research noted here, we might add ASGR1 deletion or knockdown to the growing list of possible gene therapy enhancements that one might want to undergo as the cost of such treatments falls, should the evidence for benefits without drawbacks hold up in replication studies:

According to new research, just less than one per cent of the population is naturally protected against developing chronic coronary artery diseases. The study involved 292,000 participants of European origin. Applying advanced gene sequencing techniques, the researchers located an area - a deletion - in the human genome, which lacked twelve DNA building blocks in 0.8 per cent of the participants. Subsequent cell experiments revealed that due to the deletion, the serried gene - ASGR1 - is unable to establish the normal structure and function of the protein called the asialoglycoprotein receptor. The receptor protein binds certain sugars and surprisingly, it now turns out that the receptor plays an important role in our cholesterol metabolism and potentially related to vascular inflammation, and in whether or not we develop arteriosclerosis in coronary arteries.

"What's spectacular about the discovery is the fact that individuals with this rare and particular mutation have a lower level of cholesterol in their blood and their risk of developing arteriosclerosis is 34 per cent less. In other words, just under 1 per cent of the European population is fortunate to have been born with a mutation that decreases their cholesterol levels and thus to a certain extent protects them from developing coronary atherosclerosis. The mutated protein is expressed in a part of human biology which we have not previously been focused on in our attempts to understand the mechanisms behind arteriosclerosis. This unexpected finding will undoubtedly result in many researchers examining the underlying biological systems very thoroughly; hoping to utilize this new knowledge to develop new preventive measures and treatments for cardiovascular diseases."

Link: http://healthsciences.ku.dk/news/new-2016/mutation-protects-against-heart-disease/

Telomere Length as Presently Measured Does Not Predict Atherosclerosis Risk

Average telomere length is presently measured in white blood cells from a blood sample. Telomeres, the caps of repeating DNA sequences that protect the ends of chromosomes, tend to become shorter on average with age, but also with illness: this is probably largely a reflection of stem cell activity (delivering new cells with longer telomeres) and cell division rates (telomere length reduces with each division) in the immune system, which in turn reflects some of the present state of health and age-related decline. This is a statistical observation, however, and it is has more than enough individual variation to be a pretty terrible measure of aging for any practical use. So it isn't unexpected to see observations like this one, in which average telomere length in immune cells is shown to have little to no relationship to a specific outcome in aging:

There is great interest in developing new biomarkers of cardiovascular risk that allow a more accurate risk predication than classical risk factors such as high cholesterol, smoking, physical inactivity, and high blood pressure. An estimated half of cardiovascular disease (CVD) patients do not have a high risk profile based on classical risk factors. Moreover, many individuals who score high for these risk factors do not develop the disease. There is therefore a clear need to find new biomarkers to enable the early identification of individuals who do not yet show disease symptoms but are at high risk of developing atherosclerosis and suffering a heart attack or stroke. One possible biomarker is telomere length, but a new study suggests that leukocyte telomere length (LTL) in circulating blood does not effectively predict CVD risk in individuals without disease symptoms. "These results are rather like taking a snapshot at a single point in a person's lifetime, and we still need to determine if atherosclerosis progresses faster in people who start with shorter leukocyte telomeres, have a higher proportion of very short telomeres, or in whom telomeres shorten at a faster rate during the aging process."

Numerous studies have demonstrated that telomere DNA shortens progressively as we age, leading to genomic instability and eventually cell death, especially when the telomeres become "critically" short. Telomere DNA shortening has come to be viewed as a marker not only of aging, but also of an individual's general state of health, and this has generated great interest in the possibility that telomere length in circulating white blood cells might predict the risk of CVD. This idea is supported by epidemiological studies demonstrating shorter LTL in patients suffering coronary artery disease, heart attack, or stroke. However, the results obtained to date are inconclusive, especially in relation to subclinical atherosclerosis. Moreover, there is a lack of information about the possible association of CVD with a high proportion of very short telomeres.

The new study included 1459 volunteers participating in the PESA (Progression of Early Subclinical Atherosclerosis) clinical trial. In the study, the research team explored whether mean LTL and the proportion of critically short telomeres show an association with the presence and extent of subclinical atherosclerosis. In line with previous studies, the results show an association between increasing age and a lower mean LTL and a higher proportion of short telomeres (defined arbitrarily as those measuring less than 3 kilobases). However, none of these parameters showed any association with the presence or extent of subclinical atherosclerosis in the PESA cohort.

Link: http://www.eurekalert.org/pub_releases/2016-05/cndi-tli052316.php

Autophagy Somewhat Alleviates the Effects of Aging in the Heart

For many years now, since the first batch of single gene mutations that enhance longevity in short-lived laboratory species were discovered, the cellular maintenance processes of autophagy have occupied a central role in considerations of aging. The open access paper I'll link to today is focused on autophagy in the heart, and provides a good example of the reasons why autophagy is of interest to many of the researchers who search for ways to slow the progression of aging.

Aging is at root a process of damage accumulation. We are machines and we wear and break. Unlike the much simpler mechanical and electrical devices that surround us these days, however, our machinery has a great capacity for self-repair. The overwhelming majority of molecular damage and disarray that arises constantly in all of our cells is repaired very quickly. This makes the progression of damage over time a much more complicated and layered process than is the case in a car or a computer. You can look at the Fight Aging! FAQ for a high level summary, but that does no justice to the poorly understood intricacy of the ways in which the many forms of damage interact over time, and the way in which the diminished capacities or dysfunctions of specific organs and systems in the body feed into one another. Aging is perhaps as much a failure of repair systems as it is an accumulation of damage that cannot be repaired at all - though that certainly does exist in the form of cross-links that cannot be broken down, even in youth, to pick one example.

Autophagy is an important set of cellular repair systems, responsible for breaking down and recycling damaged structures, as well as some large molecules and metabolic wastes. It is a complicated arrangement of signals, detection of damage, markers for damage, processes for moving things around the cell, and specialized organelles that actually perform the dismantling. More autophagy is better for the obvious reason that it means there is less damage at any given point in time, so less of a chance for that damage to cause further issues. Many of the methods of extending life in laboratory species are associated with a higher level of autophagy in at least some tissue types. Calorie restriction, for example, the most well studied of all of the methods of somewhat slowing aging, appears to depend on autophagy for most of its benefits. Disable autophagy, and life is no longer extended by a diet lower in calories. One thing that has become very apparent from the past two decades of making various animals live modestly longer lives is that evolution has not selected for the optimal level of autophagy - or at least, longevity doesn't seem to be high on the list of factors determining that optimal level.

Thus many researchers are interested in producing some kind of therapy that can upregulate autophagy in humans, and for all the same reasons that many researchers want to build drugs that can mimic calorie restriction or mimic exercise. The idea is to modestly slow aging, as even a small gain would would produce enormous economic benefits when spread across the whole population. For me, this is thinking too small, and people should focus on repair and rejuvenation that can add decades for the same cost, but this SENS view of rejuvenation research is still fighting its way to the mainstream. Most researchers focus on slightly slowing aging as a goal, where they are interested in treating aging at all. Oddly, despite many years of working towards drug candidates that might induce greater autophagy, and a stream of research that always looks on the verge of going somewhere, there has been very little progress towards the clinic. The tone of the paper quoted below is very similar to work written ten or fifteen years ago, and yet the therapies are not here yet:

Aging and Autophagy in the Heart

Because the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as autophagy) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by the accumulation of misfolded proteins and dysfunctional organelles. On the contrary, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart.

Because autophagy is downregulated with age and downregulation of autophagy promotes senescence of the heart, interventions to increase the level of autophagy may prevent or slow the progression of aging in the heart. Furthermore, considering the fact that cardiac aging is accompanied by the accumulation of insoluble polymeric materials, such as lipofuscin, and damaged organelles, it would seem to be advantageous to have a degradation mechanism with a large capacity. Interestingly, both calorie restriction (CR) and suppression of mTOR, interventions that alleviate the adverse effects of aging and increase lifespan, promote autophagy in many cell types and organs, even when autophagy is suppressed by aging. Importantly, CR has been shown to reduce age-related pathologies and diseases in animals. However, whether the beneficial effects of these interventions are mediated primarily through activation of autophagy in the heart requires further study.

Many other questions remain unanswered. First, it is unclear when the level of autophagy becomes significantly altered during the course of aging in the human heart. Currently, evaluating the level of autophagy and autophagic flux is challenging in the human heart in vivo. Developing convenient and reliable methods to accurately evaluate cardiac autophagy is essential. Second, more investigation is needed to elucidate the molecular mechanism by which autophagy or mitochondrial autophagy is regulated during the course of aging in the heart. Autophagy is regulated not only at the level of autophagosome formation but also at the levels of autophagosome-lysosome fusion and lysosomal degradation. In particular, how the function of lysosomes is affected by aging requires further investigation. Third, more investigation is needed to clarify the functional role of autophagy or mitophagy during cardiac aging. Currently, none of the available molecular interventions allow purely specific modification of either autophagy or mitophagy in mammalian cells. Currently, none of the available molecular interventions allow purely specific modification of either autophagy or mitophagy in mammalian cells. Whether protein aggregates, such as accumulated lipofuscin, are causatively involved in cardiac aging has not been formally addressed. Development of a more selective intervention or improvement of the selectivity by combining multiple interventions seems essential

Fourth, it is important to clarify the molecular mechanisms by which autophagy or mitophagy regulates cardiac aging. Although autophagy is generally thought to be a nonspecific mechanism of protein degradation, there is increasing evidence that some proteins may be specifically degraded. Fifth, most of the investigations reported to date focused only on autophagy in cardiomyocytes during aging. It is important to determine whether autophagy in other cell types, such as inflammatory cells, also affects cardiac aging and, if so, how these cells communicate with cardiomyocytes. Finally, it is essential to develop more convenient and specific interventions to normalize the level of autophagy in the heart during aging. Autophagy mediates many lifespan-extending and antisenescence mechanisms. Together with the recent advancement in understanding the molecular mechanisms of autophagy, investigating the role of autophagy/mitophagy during cardiac aging should eventually lead to the development of more efficient and specific interventions to slow senescence and increase stress resistance in the heart.

Investigating the Gut Microbiota of Extremely Old Individuals

Researchers have recently started to catalog the symbiotic microbes found in the intestines of extremely old human individuals, aiming to gain an understanding of the degree to which differences in microbial populations between individuals can influence the odds of survival in later life. The microbial environment of the gut has been shown to influence aging in various species to a great enough degree to be worthy of investigation by those scientists who seek a full understanding of how aging progresses. From a high level perspective, consider that calorie intake is one of the most influential of environmental factors when it comes to pace of aging, and the activities of microbial populations in the gut help to determine how the amount of calories consumed maps to amounts of specific molecular constituents of food passed on to the rest of the body. There are also interactions between gut microbes and the immune system that may be important, and no doubt a range of other mechanisms to consider as well.

The study of the extreme limits of human lifespan may allow a better understanding of how human beings can escape, delay, or survive the most frequent age-related causes of morbidity, a peculiarity shown by long-living individuals. Longevity is a complex trait in which genetics, environment, and stochasticity concur to determine the chance to reach 100 or more years of age. Because of its impact on human metabolism and immunology, the gut microbiome has been proposed as a possible determinant of healthy aging. Indeed, the preservation of host-microbes homeostasis can counteract inflammaging, intestinal permeability, and decline in bone and cognitive health.

Aiming at deepening our knowledge on the relationship between the gut microbiota and a long-living host, we provide for the first time the phylogenetic microbiota analysis of semi-supercentenarians, i.e., 105-109 years old, in comparison to adults, elderly, and centenarians, thus reconstructing the longest available human microbiota trajectory along aging. We highlighted the presence of a core microbiota of highly occurring, symbiotic bacterial taxa (mostly belonging to the dominant Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families), with a cumulative abundance decreasing along with age. Aging is characterized by an increasing abundance of subdominant species, as well as a rearrangement in their co-occurrence network. These features are maintained in longevity and extreme longevity, but peculiarities emerged, especially in semi-supercentenarians, describing changes that, even accommodating opportunistic and allochthonous bacteria, might possibly support health maintenance during aging, such as an enrichment and/or higher prevalence of health-associated groups (e.g., Akkermansia, Bifidobacterium, and Christensenellaceae).

Link: http://dx.doi.org/10.1016/j.cub.2016.04.016

Age-Related Y Chromosome Loss and Alzheimer's Risk

In recent years researchers have noted that a small proportion of cells in males lose their Y chromosome over the course of aging. This appears to correlate with mortality and cancer risk, among other things, though there is no good picture of why this is the case at the present time. Aging is a global phenomenon, occurring in all tissues and organs, and so most aspects of aging correlate with one another, making it challenging to pick out cause and effect. Here, researchers find a correlation between Y chromosome loss and risk of suffering Alzheimer's disease:

"Most genetic research today is focused on inherited gene variants - mutations that are inherited by the offspring, but what we're looking at are postzygotic mutations that are acquired during life. Using new tools to analyze genetic variations that accumulate with age, we can help explain how sporadic diseases like cancer or Alzheimer's manifest." One such postzygotic mutation found in the cells of biological males is the loss of the Y chromosome in a degree of blood cells. Loss of Y occurs in up to 17 percent of men and is more likely to be found in older men and men who smoke. This study expands on the idea that loss of Y, already a known risk factor for cancer, could be a predictive biomarker for a wider range of poor health outcomes, specifically Alzheimer's. Why loss of Y can be linked to an increased risk for disease remains unclear, but the authors speculate it has to do with reduced immune system performance.

The researchers looked at over 3,000 men to ascertain whether there was any predictive association between loss of Y in blood cells and Alzheimer's disease. The participants came from three long-term studies that could provide regular blood samples: the European Alzheimer's Disease Initiative, the Uppsala Longitudinal Study of Adult Men, and the Prospective Investigation of the Vasculature in Uppsala Seniors. Across the datasets, those with the highest fraction of blood cells without a Y chromosome were consistently more likely to be diagnosed with Alzheimer's. "Having loss of Y is not 100 percent predictive that you will have either cancer or Alzheimer's, as there were men in the study who had the mutation and lived with no symptoms well into their 90s. But in the future, loss of Y in blood cells can become a new biomarker for disease risk and perhaps evaluation can make a difference in detecting and treating problems early." The researchers will next investigate the effect of loss of Y in larger cohorts and explore in greater detail how it confers risk for specific types of cancers and disease. They also plan to look at the cellular changes caused by loss of Y and how it affects different types of blood cells.

Link: http://www.eurekalert.org/pub_releases/2016-05/cp-loy051816.php

Bill Andrews of Sierra Sciences Announces Collaboration with BioViva

At a recent conference, Bill Andrews of Sierra Sciences announced a forthcoming collaboration with BioViva, currently pushing regulatory boundaries to develop gene therapies as treatments for aging. A new company will be formed, BioViva Fiji, to offer gene therapies that can compensate for some of the aspects of degenerative aging via medical tourism in Fiji. The principle focus, given that this is Sierra Sciences we are talking about here, is telomerase gene therapy, but BioViva is also working on a follistatin gene therapy, and it is worth bearing in mind that in this age of CRISPR rolling out any single target gene therapy that has some background work in the research community isn't the huge technical undertaking it would have been in past years. All of the time and cost goes into a reasonable level of testing, and the only real hurdle left from a technical point of view is proving that a therapy can reliably introduce genes into a large enough number of cells to produce benefits. We're going to see a lot of work on gene therapies in the next few years - this is just the start and the tip of the iceberg.

Fiji, like many countries in the Asia-Pacific region, has been taking steps in recent years to make itself attractive as a destination for medical tourism, and thereby encourage the growth of high-end local industries that benefit from the wealth of larger and more prosperous countries. It makes a lot of sense as a long-term plan, and competition between regions for medical tourism will hopefully prevent these countries from falling into the overregulated repression of medical development found in the US and Europe, a state of affairs that slows development and that gave rise to medical tourism in the first place. Fiji is the destination for this particular effort, but it could equally have been any of a number of other choices.

"Sierra Sciences and BioViva - Liz Parrish - have now joined forces. We have started a new company, called BioViva Fiji, on Fiji island, and we are now building a large-scale production facility and a clinic to soon be able to provide a gene therapy approach towards curing aging."

Bill Andrews is, as many of you will recall, an enthusiast for telomerase and telomere length as a key to aging, and he is in full sales mode above. The goal of Sierra Sciences before the company floundered was to build a viable treatment along these lines, but they ran out of funding and then turned to selling herbal nonsense. That was a sad end for a group that was at the outset working on interesting science. Interesting, yes, but from where I stand age-related reduction in average telomere length is a marker of aging, not a cause of aging. Telomerase gene therapies most likely extend life in mice through increased stem cell activity, counteracting some of the decline in stem cell populations that occurs with advancing age. It was surprising to find that this doesn't raise the risk of cancer, as those stem cell populations become damaged by age, and their decline is generally through to be an evolved defense against cancer in later life. It may be that the general enhancement of cell activity extends to the immune system, and better immune surveillance and clearance of cancerous cells is enough to offset that raised risk due to pushing damaged cells back to work. This or any other thesis is far from proven at this point, and telomerase gene therapies in humans still seem overly risky on this count to my eyes.

I believe based on the evidence to date that telomerase gene therapy should be classed as a compensatory treatment. It is pushing a damaged engine to do more, and it may well be the case that in humans as well as mice the balance of factors brings a net improvement in the same way as do stem cell therapies, another field associated with a prospering medical tourism industry, but that is yet to be nailed down and proven. Follistatin or myostatin gene therapies are similarly compensatory. They do not address the damage that causes aging, but they compensate partially for one its effects, in this case by adding extra muscle tissue to offset that lost over time to the mechanisms of aging. Is this all useful? Yes - if you think that stem cell therapies are worth it, then you should also think that this sort of gene therapy is worth it. I'm pleased to see Bill Andrews working on something that doesn't make me sad for the waste of potential it signifies, as was the case for the end of Sierra Sciences as a legitimate scientific venture.

We should not forget, however, that telomerase therapies cannot cure aging. A lot of people would like to think that they do, but it simply isn't the case. They don't treat the causes of aging, they instead adjust a lot of factors to paper over those causes just a little bit better than the papering over that the present mainstream of medicine can achieve. Undergo a telomerase gene therapy and you may benefit in a very similar way to a stem cell treatment, but in both cases you are still aging and still damaged. You still have mitochondrial DNA damage, lipofusin in your long-lived cells, cross-links stiffening your arteries, and so on and so forth, and all those things are still killing you.

Reducing Hypertension in Old People Significantly Reduces Cardiovascular Risk

The data presented by these researchers is a compelling argument for the importance of hypertension in cardiovascular aging. Hypertension as a result of intrinsic aging processes is probably largely caused by stiffening of blood vessels, but narrowing of vessels due to atherosclerosis and other more general consequences of metabolic dysfunctions, such as those that result from being overweight, also play a part. The cardiovascular system remodels in response to hypertension, and is damaged, producing a variety of forms of cardiovascular disease. In addition, a faster pace of rupture of tiny vessels in the brain due to stiffening and increased pressure leads to dementia. All of these are good reasons to work at maintaining a lower blood pressure throughout later life, and more importantly to support the development of therapies capable of reversing the causes of blood vessel stiffening, such as glucosepane cross-link breakers.

Intensive therapies to reduce high blood pressure can cut the risk of heart disease in older adults without increasing the risk for falls. In the United States, 75 percent of people over age 75 have hypertension, which can lead to cardiovascular disease, a leading cause of disability, morbidity and death. Current guidelines have provided inconsistent recommendations regarding the optimal systolic blood pressure (SBP) treatment target in geriatric populations. The latest findings from the Systolic Blood Pressure Intervention Trial (SPRINT), which focused on ambulatory adults 75 or older, showed that adjusting the amount or type of blood pressure medication to achieve a target systolic pressure of 120 millimeters of mercury (mm Hg) reduced rates of cardiovascular events - heart attack, heart failure and stroke - by almost a third and the risk of death by almost a quarter, as compared to a target systolic pressure of 140 mm Hg.

The 2,636 participants were randomized to an intensive target systolic blood pressure (SBP) treatment target of 120mmHg or the standard target of SBP of 140 mmHg. People with diabetes or heart failure were not included in the trial. At the beginning of the study, people underwent blood pressure measurement three times in a quiet room, completed a walking test to determine gait speed, and responded to a questionnaire to categorize their level of frailty. Blood pressure was rechecked every three months and medication adjusted as needed. Both groups also were checked for eight potential complications of lower blood pressure, such as hospitalizations, falls, acute kidney injury and fainting. The researchers found no difference between the two groups in these areas. On average, persons in the lower blood pressure goal group required one additional medication to reach goal.

"These findings have substantial implications for the future of high blood pressure therapy in older adults because of its high prevalence in this age group, and because of the devastating consequences high blood pressure complications can have on the independent function of older people. Most of the medications used in SPRINT were generic, so this is a fairly inexpensive way to help prolong the time that people can live independently in their homes and avoid those common conditions that often cause a person to have to move to higher level of care or an institution."

Link: http://www.wakehealth.edu/News-Releases/2016/Lowering_Blood_Pressure_Reduces_Risk_of_Heart_Disease_in_Older_Adults_Without_Increasing_Risk_of_Falls.htm

An Interview with Robert Young of the Gerontology Research Group

Here one of the long-standing core members of the Gerontology Research Group (GRG) is interviewed. This volunteer organization maintains and validates records of supercentenarians, those rare individuals who live past 110, and also runs one of the few online watering holes for the aging research community. Unfortunately, the interviewer is overly flippant on the topic of aging and longevity, but that can be skipped in favor of the more interesting portions of the interview:

What's the goal of the GRG? Do you want to live forever?

So basically at the moment it has two main departments. One is run by the successor of Dr. Stephen Coles, who founded the GRG in 1990 and passed away in 2014 at the age of - unfortunately - only 73. The goal was for other scientists to get together and discuss the aging process and discuss potential treatments for the aging process. The idea at the time was that Western medicine was too focused on treating the symptoms of aging and not focused on treating the causes of aging. The idea was that if you put a bunch of bright minds together, you would get good results.

What's the history of age validation?

It started in the 1800s with life insurance policies. Actuaries were trying to figure out how long people lived to calculate rate for those policies. Except for the small niche field of actuarial research, very little research was done into supercentenarians. There was no database when the GRG decided to start keeping track in 1998. About 1 in 5 million people in the US are 110 and older, and before the internet came along there was no way to assemble someone that rare into data groups. But when the internet came along, we could get information from all over the world, and it became viable to study them as a population group. Things have changed so fast since the GRG went online in 1995, almost 21 years ago. Smart phones came around 2007, 2008. Go back to 2004 and ancestry.com only had 20 percent of the US census data online. Go back to 2000 and if you wanted to find a document on an extremely old person, you had to use the old hand-crank newsreel. Wow. It could take hours upon hours to look on every line of every page.

I feel like there's a story every month about the world's oldest person dying.

So here's the thing. There's a misconception that the world's oldest person dies all the time. Not true. Since Guinness started keeping track in 1955, the average length of reign has been about 1.6 years. Part of the problem though is that we do have unverified claims of people saying they're older than the oldest person and that gets reported by the media. You also get what's called the longevity myth, which is where people's imaginations exceed reality. So if you don't have a record of when you're born and you're gonna guesstimate your age, and after the age of 80, people begin to inflate their age.

Give it to me straight. What is the longest I could possibly live?

Scientifically speaking, the odds of living to 127 at the moment are one in a trillion, which means it's not happening. Living to anywhere between 115 and 120, you have what I call "probable impossible," I'd say there's about a 1 percent chance, but there's still a possibility. Between 120 and 127, the odds of surviving really begin to disappear totally. When we look at the statistics, we have currently 2,500 cases of people 110 plus. Of those, by the age of 118, only two. When you're going from 2,500 to two in just eight years, to me that's scary. Humans seem to have a warranty period of about 100 years. The average cell divides every two years. Cells divide about 50 times. To get to 115, you'd have to age about 15 percent slower than normal. Basically, Jeanne Calment, who lived to be 122, was called the Michael Jordan of aging. The point was that all the practice in the world isn't gonna make you play basketball like Michael Jordan. OK? On the other hand, if Michael Jordan never practiced, he wouldn't be as good as he was. So you have to fulfill your potential by trying to do the best you can do, but at the same time, you can't make yourself a longevity star.

Do you get the sense that it's even worth living that long? Is there any quality of life at 115?

I've probably met over 50 who are 110 plus. It can vary. One of the things that's clear to me is that you can't put them all in one category. We had one woman who was 116 who lived in her own home, she could walk with a walker, she ate Wendy's, she watched TV, she could do an interview. That's the ultimate extreme case of living well and hanging out with the great, great grandkids. On the other hand, we had a woman who was confined to bed for 21 hours a day, awake for only three, unable to get up. That's a sad situation where maybe it's not worth it. Most people are somewhere in the middle. One more thing I wanna say is that the people who live the oldest are in the best shape. So almost everybody that lives to be 115 was living on their own at 100. So we need to get rid of this idea of, "I'm gonna be 30 years in a nursing home." It's not like that.

Link: http://www.vice.com/read/we-spoke-with-the-scientist-studying-how-to-live-as-long-as-possible

Media Attention for the Dog Aging Project and Other Trials of Drugs to Modestly Slow the Progression of Aging

The Dog Aging Project launched last year, and is lavished with attention in this long press article. The initiative is a combined advocacy and research program intended to trial in pet dogs the small range of drug candidates - such as rapamycin - that have good data in mice to support both safety and the ability to modestly slow aging. In addition to the scientific side of things, this is a way to pull in more interest for the development of treatments for aging, and to gather greater support for moving to human studies. In that the goals of the Dog Aging Project are much the same as the human trial of metformin as a treatment to slow aging that is presently in the works. The bottom line is that we - the research and advocacy community - still have a long way to go when it comes to persuading the public, large funding institutions, and regulators that living longer through medical science is possible, plausible, and desirable.

Given the subject, the article here is narrowly focused on one particular view of aging and how to treat it. The scope is (a) traditional drug discovery and development, (b) slightly slowing the progression of aging by altering the operation of cellular metabolism, and (c) the prospect of a long, expensive slog to very marginal gains at some point in the decades ahead. This is a vision of the future in which humans gain a couple of years of additional healthy life sometime around 2030 because they can take a drug derived from or of a similar class to rapamycin. So on the one hand I think it is great that we now see more lengthy articles from the journalistic community that sensibly discuss both the treatment of aging and specific initiatives in aging research. It is also great that researchers are creating these innovative ways to both accomplish the science and attract more attention to the field. But at the same time, this particular approach of drug development and metabolic tinkering is an expensive and slow road to nowhere special. If it were the only path ahead, then fine, but it isn't. There is an entirely separate approach to treating aging based on targeted repair of cellular and molecular damage that could, if funded well, produce far greater gains in healthy life span for the same investment in money and time, as well achieving rejuvenation in the old.

You don't have to look far to see striking comparisons. Billions have been spent on trying to make drugs to slow aging out of sirtuins for example, and that collection of initiatives is an exemplar of the metabolic tinkering approach, hyped in its day. Yet the only concrete result has been to gain knowledge of a small slice of metabolism and its response to calorie restriction - no gain in health life or method to achieve that end has emerged. Meanwhile, for a tiny fraction of that sum, and in half the span of years, researchers taking the damage repair approach of clearing senescent cells in old tissues have already demonstrated robust benefits to health and life span in rodent studies. The pace of progress, the cost of progress, and the potential gains are night and day when comparing these two strategies. The type of longevity research that is carried out over the next few years matters greatly - our lives depend on the outcome.

Dogs Test Drug Aimed at Humans' Biggest Killer: Age

Ever since last summer, when Lynn Gemmell's dog, Bela, was inducted into the trial of a drug that has been shown to significantly lengthen the lives of laboratory mice, she has been the object of intense scrutiny among dog park regulars. The trial represents a new frontier in testing a proposition for improving human health: Rather than only seeking treatments for the individual maladies that come with age, we might do better to target the biology that underlies aging itself. While the diseases that now kill most people in developed nations - heart disease, stroke, Alzheimer's, diabetes, cancer - have different immediate causes, age is the major risk factor for all of them. That means that even treatment breakthroughs in these areas, no matter how vital to individuals, would yield on average four or five more years of life, epidemiologists say, and some of them likely shadowed by illness. A drug that slows aging, the logic goes, might instead serve to delay the onset of several major diseases at once.

But scientists who champion the study of aging's basic biology - they call it "geroscience" - say their field has received short shrift from the biomedical establishment. And it was not lost on researchers that exposing dog lovers to the idea that aging could be delayed might generate popular support in addition to new data. "Many of us in the biology of aging field feel like it is underfunded relative to the potential impact on human health this could have," said Dr. Matt Kaeberlein, who helped pay for the study with funds he received from the university for turning down a competing job offer. "If the average pet owner sees there's a way to significantly delay aging in their pet, maybe it will begin to impact policy decisions."

"I would resist the idea that we should shift funds away from cancer and diabetes and Alzheimer's, where there are clear drug targets, and say, 'We're going to work on this hypothesis,' " NIH Director Dr. Francis Collins said. "If you had a lot of money for geroscience right now, it's not clear what you would do with it that would be scientifically credible." Researchers in the field, in turn, say they might have more to show for themselves if they could better explain to Congress and the public why basic research on aging could be useful. "People understand 'my relative died of a heart attack, so I'm going to give money to that,' " said Dr. James L. Kirkland, a Mayo Clinic researcher. "It's harder to grasp 'my relative was older, that predisposes them to have a heart attack, so I should give money to research on aging.'"

Some companies have embraced the quest for drugs that delay aging. Google created Calico (for California Life Company) in 2013 with the goal of defeating aging. A start-up called UNITY has said it will develop drugs based on new research on aging mice suggesting that purging certain cells can extend a healthy life span. And a group of academic researchers is trying to persuade the FDA to recognize aging as a disease for which a drug can be marketed, which they hope will draw more interest from pharmaceutical firms. The agency recently greenlighted its proposed trial of a widely used diabetes drug, metformin, to see if it can delay the onset of other age-related diseases in older adults who have received a diagnosis of at least one, as one study suggests it might. But the group has yet to secure funding. One reason, the researchers say, is that the notion that aging is immutable is so deeply entrenched. "When I go out and try to raise money for this, the first thing people will say to me is, 'Eh, we're all getting older,' " said Steven Austad, a researcher at the University of Alabama.

Announcing Success in the MitoSENS Project Crowdfunded at Lifespan.io in 2015

I'm very pleased to report that that the SENS Research Foundation project on mitochondrial allotopic expression (MitoSENS) that was crowdfunded at Lifespan.io this time last year has achieved success. The two target mitochondrial genes have been moved to the cell nucleus, and suitably altered so that the proteins produced return to the mitochondria. This means that cells so treated are immune to age-related damage to those two genes in the mitochondrial genome: they will still construct and make normal use of the proteins encoded in those genes as though nothing happened. Given that mitochondrial DNA damage is an important contribution to the aging process, progress on this front is very welcome.

The crowdfunded work was the final sprint at the end of a years-long project conducted with minimal funding, and it is great to see success. Congratulations are due to the researchers involved. There are thirteen mitochondrial proteins in total that are thought to be all that is needed to move into the nucleus. Allotopic expression of one other mitochondrial gene is solidly complete, and is the basis for the therapies under development at Gensight. Another two genes are somewhere in the middle of the process in the SENS Research Foundation network of researchers. This leaves a further eight genes to go. As ever, this is work that is in search of much greater funding: the researchers are always ready to go, and the more that we can do to help deliver that funding, the sooner we'll see rejuvenation therapies in the clinic.

Note that you may need to click the updates tab on the fundraiser page in order for the updates to load:

Hi everyone, it's been an amazing few months. In short, we have been tremendously successful in our efforts to rescue a mutation in the mitochondrial genome! Essentially we've shown that we can relocate both ATP6 and ATP8 to the nucleus and target the proteins to the mitochondria. We can show that the proteins incorporate into the correct protein complex (the ATPase) and that they improve function resulting in more ATP production. Finally, we show that the rescued cells can survive and grow under conditions which require mitochondrial energy production while the mutant cells all die.

We have finished writing up our results and submitted them for review and publication. It may take a while for our results to be published (the peer review process can be lengthy) but as soon as it is I'll post an update here so you can see the full paper. We have also started the project that you helped us get to our stretch goal on. We have made all the combinations of mitochondrial targeting sequences with ATP6 that we proposed and are now working on testing them. I'll let you know when we know more. Thank you so much for your support!

Link: https://www.lifespan.io/campaigns/sens-mitochondrial-repair-project/#updates

Using Neural Networks on Blood Samples to Develop Biomarkers of Aging

The authors of the open access paper linked here are training neural networks on large numbers of blood samples in an effort to produce biomarkers of aging. This is an interesting approach, primarily because it should in theory answer the question of whether a given data set - such as the data from blood tests - has any useful correlation with age. Biomarkers of biological age, how damaged an individual happens to be, are a necessary development in the field of aging research. At present the only reliable way to see how well a possible rejuvenation therapy works is to wait and see, which is slow and expensive in mice and out of the question in humans. What is needed is a quick measurement that accurately reflects biological age and thus remaining life expectancy. Given that, many more potential approaches to treating aging could be assessed and compared for a given level of funding and time, as the need to wait and see could be eliminated.

One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. To make this deep network ensemble available to the public, we placed our system online (at www.aging.ai), allowing any patient with blood test data to predict their age and sex.

The best performing DNN in the ensemble demonstrated 6.07 years mean absolute error in predicting chronological age within a 10 year frame, while the entire ensemble achieved 5.55 years mean absolute error. The analysis of relative feature importance within the DNNs helped deduce the most important features that may shed light on the contribution of these systems to the aging process, ranked in the following order: metabolic, liver, renal system and respiratory function. The five markers related to these functions were previously associated with aging and used to predict human biological age. Another interesting finding was the extraordinarily high importance of albumin, which primarily controls the oncotic pressure of blood. Albumin declines during aging and is associated with sarcopenia. The second marker by relative importance is glucose, which is directly linked to metabolic health. Cardiovascular diseases associated with diabetes mellitus are major causes of death within the general population. Current and future directions of this work include adding other sources of features including transcriptomic and metabolomics markers from blood, urine, individual organ biopsies and even imaging data as well as testing the system using data from patients with accelerated aging syndromes, multiple diseases and performing gender-specific analysis.

Link: http://www.impactaging.com/papers/v8/n5/full/100968.html