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- Program and Speakers Announced for Undoing Aging, March 2018 in Berlin
- Request for Startups in the Rejuvenation Biotechnology Space, 2018 Edition
- Even Where Exercise is Shown to Help, it is Challenging to Identify the Exact Biochemistry Responsible
- How Effective are Mesenchymal Stem Cell Therapies for Age-Related Joint Issues?
- A Look Back at the Science of Longevity and Advocacy for Rejuvenation in 2017
- An Interview with Aubrey de Grey, Focused on the Science of Rejuvenation Therapies
- An Illustration of the Cost of Aging on Individual Health and Survival
- Mapranosis: the Influence of Commensal Microbes on Neurodegenerative Disease
- Summarizing the Current Understanding of Immunosenescence
- Reduced FOXO3 in Lung Fibrosis Points to Cellular Senescence
- BioViva Illustrates the Tension Between Progress and Regulation
- Tissue Engineering of Better, More Correctly Structured Kidney Organoids
- Eotaxin-1 as a Potentially Damaging Factor in Old Blood
- VCP Discovered to be Important in Cardiac Hypertrophy
- Telomere Length as Presently Measured is Not a Useful Biomarker of Aging
Program and Speakers Announced for Undoing Aging, March 2018 in Berlin
There is still time to sign up for the Undoing Aging event in Berlin, coming up in March 2018. This scientific conference will focus on rejuvenation research in the same manner as the SENS conference series that ran from 2003 to 2013 under the auspices of the Methuselah Foundation and, later, the SENS Research Foundation. Undoing Aging is a collaboration between the SENS Research Foundation and Forever Healthy Foundation, the latter being the organization founded by SENS patron Michael Greve. You might recall that in 2016 Greve pledged 10 million to fund rejuvenation research and resulting startup companies, becoming the first donor to the SENS Project|21 initiative.
As the first rejuvenation therapies near human trials and clinical availability, it becomes ever more important to expand the size of the research community presently working on ways to repair the causes of aging. As Aubrey de Grey has pointed out, there is a great deal left to accomplish on the way to a toolkit of therapies capable of turning back aging and extending healthy life spans by even a few decades. That work requires funding, and interested researchers, public support. That in turn requires networking, persuasion, and a showcasing of promising work currently in progress. In years to come, everyone will say that the strategy of repairing the cell and tissue damage of aging was obvious in hindsight - but we need their support now, when it matters, when there is work yet to accomplish, not after the fact. It is the eternal challenge of bootstrapping a movement, an industry, a research community. Conferences play an important role in this process.
Undoing Aging 2018 Conference Announces Program and Speakers
The SENS Research Foundation and the Forever Healthy Foundation today announced the 2018 Undoing Aging Conference program and speakers. Undoing Aging will take place March 15 - 17, 2018 at the Umspannwerk Alexanderplatz in Berlin, Germany. Undoing Aging 2018 is focused on the cellular and molecular repair of age-related damage as the basis of therapies to bring aging under full medical control. The conference, a joint effort of SENS Research Foundation and Forever Healthy Foundation, provides a platform for the existing scientific community that already works on damage repair and, at the same time, offers interested scientists and students a first-hand understanding of the current state of this exciting new field of biomedical research.
Undoing Aging 2018 Program
I have regretted not having thought of the title "Undoing aging" for our 2007 book "Ending Aging", ever since a reader accidentally used that name for it in an email to us. I am thus delighted to have this opportunity to use it now. It perfectly encapsulates the nature of the approach to maintaining youthfulness in old age that SENS Research Foundation pursues: the repair of the self-inflicted damage that the body generates as side-effects of essential metabolic processes. This conference will, accordingly, mirror the structure of SENS, with sessions devoted to each strand and to the enabling technologies that multiple strands will rely upon. Those of you who attended any of the conferences we organised in Cambridge, from 2003 to 2013, will notice the similarity - and indeed, the similarities will not end there!
Two of the seven SENS damage categories consist of the elimination of cells that we have too many of: either because they are dividing too much (which is essentially the definition of cancer) or because they are not dying when they should. The most promising truly general anti-cancer therapies each merit multiple talks, so we have a session for each, as well as one for the "death-resistant cells" category. Russell and Hawthorne will present novel methods for weakening the ability of cancer (or indeed any) cells to render themselves invisible to the immune system, while Silva and Gorbunova will update us on ways to manipulate telomere elongation and thereby limit proliferation capacity. Kirkland, Lewis, and de Keizer will then discuss the range of methods currently under development for selectively eliminating cells that are doing us more harm than good: small molecules, suicide genes, and engineered peptides.
The two SENS categories that have, arguably, seen the greatest contribution from research funded by SRF are those relating to damage within cells: mitochondrial mutations and "garbage". Our in-house team has made immense progress recently in rendering mitochondrial mutations harmless by installing "backup copies" in the nuclear genome, and O'Connor will provide updates on where that work stands. Honkanen and Moody will describe the state of play in relation to elimination of the two best-characterised types of intracellular garbage that drive major age-related diseases, namely atherosclerosis and macular degeneration.
Extracellular changes play a major role in mediating the loss of function of cells and tissues. Talks in this part of the conference will cover a variety of such problems. Paul and Graef will present novel approaches to the removal of aggregated material, notably the protein transthyretin which misfolds particularly easily and may be the main factor responsible both for important diseases and for mortality in very old age. Spiegel and Clark are both researching the stiffening of the extracellular matrix, a process that contributes both to life-threatening and to cosmetic aspects of aging. Wagers' focus will be the role of circulating proteins in mediating and counteracting age-related deleterious changes of gene expression in a wide range of tissues.
In an ideal world, the whole of SENS would be viewed as regenerative medicine, since it is all about restoring structure to restore function; but that term has too much history to be broadened in such a way, so we adhere to its standard usage covering just stem cell therapy and tissue engineering. The manipulation of stem cells to generate safe and effective therapeutic reagents has advanced by leaps and bounds recently, and West, Sen, and Loring are among the absolute leaders in this burgeoning area, especially where age-related conditions are concerned.
The replacement of entire organs from a variety of sources may soon be far more practical than hitherto, and Atala, Lemaitre, and Jones will describe three radically new approaches to addressing the still-acute shortage of organs for transplant. Finally, the restoration of organ function can in principle be achieved not only via one-for-one replacement of a malfunctioning organ, but through more distributed means where a single "organoid" only partially substitutes; Lagasse will present one highly novel approach along these lines.
Most of SENS is still at a pre-clinical stage of development, where evidence of safety and efficacy can be obtained via short cuts that would not be available when treating humans. SRF has, therefore, always set its priorities both near-term and long-term, funding proof-of-concept research alongside work that will only have clear utility further downstream. The latter tend to cross the boundaries between SENS strands. First, it is crucial to be able to measure efficacy across the full range of metabolic markers, and Horvath, Fortney, and Csordas will address three complementary "omics" domains in which changes with age - and therapeutic manipulations of those changes - can be monitored: epigenomics, metabolomics, and proteomics. Then we will hear, from Young and Zhavoronkov, how drugs can be discovered and repurposed using state-of-the-art computational techniques. Finally, how are therapeutics delivered? The conference's closing session will feature Calos, Scholz, and Hebert telling us about new ways to get nucleic acids, proteins, and cells (respectively) into places that standard methods can only inadequately reach.
Request for Startups in the Rejuvenation Biotechnology Space, 2018 Edition
A shift in the character of rejuvenation research has taken place over the past couple of years. Greater attention is being given to this work, and the most advanced lines have made - or will soon make - the leap from non-profit laboratory and philanthropic funding to for-profit startup company and venture funding. A growing community of angel investors and a fair few venture funds are now interested in supporting startup companies whose founders implement approaches to rejuvenation that follow the SENS model of repairing fundamental damage. A brief selection includes Kizoo Technology Ventures, Methuselah Fund, the Longevity Fund, Mann Bioinvest, and Apollo Ventures. Others will join them in the next year or two - it is a growing area of interest.
The point to be made here is that there is more than enough funding waiting in the wings to power any credible rejuvenation-focused company through its first few years. It is in fact much, much easier at this point to raise that funding than it is to obtain philanthropic funding for early stage research in the laboratory. The message for those with technologies that can make the leap is to go ahead and do it. Don't wait around; reach out to the venture community and take a look at the present state of play. Many different and interesting approaches to the treating of aging as a medical condition are on the verge of viability for commercial development, and what follows is a list of those I'd like to see emerge sooner rather than later, in no particular order of priority. If you are working on something that looks a lot like any of the following, then please do reach out; there are many in our community who would like to hear from you.
Better Approaches to Assessing the Outcome of Senolytic Treatments
Senolytic therapies that destroy senescent cells are going to be a very big deal in medicine. But how to determine whether or not they are working, and how well they work? One can measure all the usual metrics of disease, but that is a poor second best to understanding the actual load of senescent cells, and therefore the degree of impact. Currently all of the useful ways to count senescent cells involve tissue samples, and since wounding creates senescent cells there is some question as to the viability of biopsy-based approaches. We need some better: approaches that will lead to non-invasive or minimally invasive tests that quantify cellular senescence. A couple of years from now there will be a dozen companies putting forward various senolytic treatments, but next to no-one appears to be thinking about viable commercial assays for senescence. In such an important space, there is currently a single startup and perhaps one or two research groups with interesting ideas. This needs to change.
Make Medical Tourism Work for Enhancement Therapies
If any of the first generation senolytic drug candidates prove useful in humans, that will result in a tremendous market opportunity for medical tourism. The same is true when, in the next few years, CRISPR-based approaches to gene therapy become capable of reliable transfection of a large fraction of target cells. There are four or five gene targets, such as myostatin and follistatin, that make for very interesting enhancement therapies. There are many, many more healthy people who might want to undergo rejuvenation or enhancement therapies than there are patients seeking treatments for specific medical conditions. A number of groups related to the longevity science community have been gnawing away slowly at various aspects of the challenge of making medical tourism work, such as BioViva, Ascendance Biomedical, and Libertas Biomedical, and all have found it harder than one might suppose it to be. Somewhere in here there is a recipe that works, a way to make overseas clinical trials and treatments transparent, cost-effective, safe, and attractive, building a growth market that works in synergy with the advent of practical rejuvenation therapies and enhancement technologies.
Rejuvenating the Immune System
The immune system touches on so very many processes and aspects of aging that turning back its age-related dysfunction will be enormously influential on health in later life. There are potentially viable approaches for each of the various parts of this puzzle, and most of them are within striking distance of commercial development. Selective destruction of errant immune cells, or even the entire immune system, if it can be done without the present working approach of high dose, damaging immunosuppressants. Periodic infusion of patient-specific immune cells in bulk. Addressing the failing activity of the bone marrow stem cell populations responsible for creating immune cells. Restoring activity to the thymus, where T cells mature, to increase the supply of new T cells. Immune dysfunction is a sizable component of age-related frailty, and any of these items should move the needle.
Glucosepane Cross-Link Breaking and Supporting Technologies
At some point in the near future, the Spiegel Lab staff will uncover enzymes to break glucosepane cross-links, and then no doubt roll that effort into a startup company. There are probably numerous other approaches that will work, however, such as suitable small molecule drugs. As cross-link breaking will reverse blood vessel stiffening and skin aging, it will be an enormous market with plenty of room for competition. Drug screens are not massively expensive, though getting set up to work with glucosepane is still a specialty concern; there is a real opportunity here for any group that can adapt to the developing infrastructure for glucosepane research and make some progress. Further, this field has the same challenge in measurement of outcomes as senolytics: while companies will start by forging ahead with therapies, how do we tell how greatly a specific individual is affected by glucosepane cross-linking without cutting chunks out of them for analysis? Non-invasive or minimally invasive means of assessment will be important, and very much in demand as the first therapies roll out.
Better, Faster, Cheaper Amyloid Clearance
Current immunotherapy approaches to the amyloid-β of Alzheimer's disease are characterized by their enormous expense, both in development and implementation. Unless the cost is crushed down quite radically, and unless the pace of progress towards something that actually works speeds up to the same degree, this will be a poor platform for the future clearance of the other twenty or so types of amyloid that build up in aged tissues. We need to do better than this. More thinking outside the box is needed, such as the cerebrospinal fluid drainage focus of Leucadia Therapeutics or the catabodies of Covalent Bioscience, both approaches that could be far more economically viable if successful. More similarly inventive biotechnologies are called for.
Clearing Out as Yet Untouched Forms of Lysosomal Garbage
Companies such as human.bio and Ichor Therapeutics are working on some of the first implementations of biotechnologies to break down specific problem forms of metabolic waste, those that clog up the lysosomal recycling mechanisms, or otherwise cause cells to become dysfunctional. This is a small start on a sizable challenge: there are a great many problem compounds, and thus a great many opportunities to make meaningful inroads in removing these contributing causes of age-related disease. The Ichor Therapeutics model of picking one compound strongly tied to a specific disease is a strategy that can probably sustain a dozen companies for a variety of targets given the current state of knowledge.
Components of an Ecosystem for Targeted Blockade of Telomere Lengthening
Defeating all cancer with one single form of therapy, based on blockade of telomere lengthening, is a very plausible solution to the problem of too many types of cancer, too few researchers, and the current mainstream focus on overly specific forms of cancer treatment. If we want to see meaningful progress to an end to cancer in our lifetimes, the existing research and development model must change. The scientific path forward to this class of universal cancer therapy is well defined: selectively block the effects of (a) telomerase and (b) the alternative lengthening of telomeres (ALT) mechanisms, and couple that with a targeted delivery mechanism. It is unlikely at this stage that any one company could move directly to the full unified approach as a product, but a solution for even part of the overall problem, the portion of the final ecosystem, should be valuable in and of itself. That is likely to start with one of the demonstrated means of sabotaging telomerase activity, but we shall see.
Bringing Cell Therapies into the Rejuvenation Space
Today the overwhelming majority of cell therapies used in clinics do not produce rejuvenation. They achieve temporary benefits in patients largely through reductions in inflammation, accompanied by modest increases in regeneration and tissue maintenance that would not otherwise have taken place. The transplanted cells die quickly, and achieve these results through signaling in the period of time that they remain alive. The next generation of more sophisticated cell therapies is still waiting in the wings, approaches that can actually replace lost or damaged cell populations for the long term, with transplanted cells that survive and integrate into tissues, in order to restore function to specific organs and biological systems. Further, there are a range of other less immediately obvious possibilities that may also prove useful, such as induction of pluripotency in vivo, the aforementioned infusion of patient-matched immune cells, and accelerated cell replacement strategies. All in all, stem cell based regenerative medicine is a field that has reached a comfortable point, a box, and now needs to break out of it to reach the next level.
Reliable, High-Coverage Gene Therapy Platforms
The big stumbling block for moving the most promising genetic edits direct to human access via medical tourism is the reliability and cell coverage of the delivery methods when used in adult individuals. They are not consistent enough, and they are not delivering the payload into a large enough fraction of cells - and particularly stem cells, needed to make any change truly permanent for the recipient. Success here would be transformative for medicine and human enhancement technologies, and it appears that the research community is on the verge of solving this challenge in a number of different ways. Any one of these methods, carried forward to the clinic, should be enough to unlock an explosive growth in the size and capabilities of the gene therapy marketplace.
Even Where Exercise is Shown to Help, it is Challenging to Identify the Exact Biochemistry Responsible
Physical exercise is good for long term health, and thus the research community is interested in finding ways to recreate its benefits without the need for exertion. The prospect of exercise mimetic drugs should sound like a familiar sort of goal, and it is. This line of development almost exactly recapitulates earlier years of the long-running effort to find ways to recapture the beneficial response to calorie restriction via pharmaceuticals. Both are immensely challenging projects, consuming enormous effort and funding with little to show for it but incremental progress in mapping slices of cellular biochemistry. The search for calorie restriction mimetics is going on for two decades old at this point, and has cost something like a billion to date. It remains the case that there is no credible drug in the clinic, and a lot more of the relevant portions of cellular metabolism are yet to mapped.
The same process of mapping and initial drug evaluation that has been underway for many years for calorie restriction has really only just started in earnest for exercise, despite a few threads of research stretching back just as far, so we shouldn't be holding our breath waiting for pharmaceuticals to enable cardiovascular fitness without the physical exertion. At the present pace, advanced rejuvenation therapies that can turn back aging by reversing its causes will be contemporary with methods of tinkering with the operation of metabolism to somewhat improve health. It makes you wonder why the effort - but the answer to that is probably the as yet incomplete detailed map of cellular biochemistry. The true scientific goal is knowledge, not application of knowledge. If you want application, technology, and consideration of which paths forward might be more effective than others when it comes to health, then the pure science community is probably not the right place to be looking.
The research here is illustrative of the point. Given an age-related condition where exercise has been shown to be helpful in specific ways, is it possible to chase down exactly why exercise helps? The answer is that, given a few years, a research group can make some inroads, and then come to a stage at which a lot more work will be needed to progress further. Cellular biochemistry is enormously complex, and exercise influences nearly every aspect of the way in which cells work. Chasing the relationships between regulators and actors and systems and cellular behaviors, all of this in an environment of great complexity, is laborious and time-consuming. In the long run there is no such thing as useless knowledge, and the scientific aim of complete knowledge is correct and noble, but other strategies are needed if we want to achieve sizable gains in human health and longevity in the near term.
Researchers shed light on why exercise slows Parkinson's
While vigorous exercise on a treadmill has been shown to slow the progression of Parkinson's disease in patients, the molecular reasons behind it have remained a mystery. Now, for the first time in a progressive, age-related mouse model of Parkinson's, researchers have shown that exercise on a running wheel can stop the accumulation of the neuronal protein alpha-synuclein in brain cells. Clumps of alpha-synuclein are believed to play a central role in the brain cell death associated with Parkinson's disease.
The mice in the study, like humans, started to get Parkinson's symptoms in mid-life. At 12 months of age, running wheels were put in their cages. "After three months the running animals showed much better movement and cognitive function compared to control transgenic animals, which had locked running wheels." Researchers found that in the running mice, exercise increased brain and muscle expression of a key protective gene called DJ-1. Those rare humans born with a mutation in their DJ-1 gene are guaranteed to get severe Parkinson's at a relatively young age. The researchers tested mice that were missing the DJ-1 gene and discovered that their ability to run had severely declined, suggesting that the DJ-1 protein is required for normal movement. "Our results indicate that exercise may slow the progression of Parkinson's disease by turning on the protective gene DJ-1 and thereby preventing abnormal protein accumulation in brain."
Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson's disease
DJ-1 is one of the Parkinson-associated genes in which mutations lead to early-onset, autosomal recessive disease. Because the loss of gene expression causes disease, the DJ-1 gene can be seen as protecting nearly everyone from developing Parkinson's disease. DJ-1 or its homologs are present in all life forms that use oxygen including all animals, all plants that perform photosynthesis, and all aerobic bacteria. This critical gene protects cells by antioxidant mechanisms such as stabilizing Nrf2 (nuclear factor erythroid 2-related factor) and thereby upregulating a family of antioxidant response element (ARE) genes. DJ-1 is also involved in regulating HIF1 transcriptional activity under hypoxic conditions. We have shown that DJ-1 also protects cells from abnormal protein aggregation by upregulating Hsp70.
Because Parkinson's disease leads to disabling bradykinesia and rigidity, exercise and physical therapy are often prescribed by physicians. The hope has been that exercise will enhance mobility, preserve muscle tone, and prevent medical complications such as pneumonia that are associated with immobility. Several clinical trials have found that regular exercise or physical therapy may improve motor function in Parkinson patients. In acute, drug-induced animal models of Parkinson's disease, exercise can partially protect dopamine neurons from neurotoxicity.
We have discovered that a functional DJ-1 gene is required for normal, voluntary running wheel performance in mice. In young wild-type mice as well as in aging transgenic mice expressing mutant human α-synuclein in all neurons, running wheel exercise can increase DJ-1 protein levels in muscle, plasma, and brain. We have found that long term running wheel exercise has a neuroprotective effect in our transgenic mice. Exercise significantly improves motor and cognitive function while dramatically reducing α-synuclein oligomer accumulation in brain while increasing plasma concentrations of α-synuclein. The mechanism by which exercise leads to these beneficial effects appears to be related to upregulation of DJ-1 and other neuroprotective factors such as Hsp70 and BDNF in the brain.
Because exercise produces sweeping changes in all aspects of physiology from sensorimotor activity to lipid metabolism in muscle, it is difficult to define a hierarchy of beneficial effects on brain function. Since mice which lack the DJ-1 gene cannot perform on running wheels with the same intensity as wild-type animals, DJ-1 appears to be essential for dealing with the physiological stress created in muscle by sustained motor activity. Because DJ-1 knockout animals have the same cognitive performance as wild-type mice, the DJ-1 deficit does not appear to influence cognition nor low intensity motor activity. To precisely define the role of muscle verse brain derived DJ-1, organ-specific DJ-1 knockouts would have to be developed.
Our study gives insight into the mechanism by which exercise prevents α-synuclein oligomer accumulation in brain. While oligomer formation was reduced in brains of mice with access to running wheels, the same animals showed increased plasma concentrations of α-synuclein monomers and dimers. α-Synuclein is known to be present in plasma of humans and other mammals, but the exact source of plasma α-synuclein remains uncertain. While it is possible that red blood cells may release α-synuclein into plasma, the protein may come from central and peripheral neurons.
In summary, we have found that voluntary exercise on a running wheel can upregulate DJ-1 in muscle and brain of a transgenic mouse model of Parkinson's disease and can prevent the age-related decline of motor and cognitive abilities normally seen in this transgenic strain. Since we have described similar beneficial effects with the drug phenylbutyrate in these transgenic mice, we hypothesize that patients with Parkinson's disease might be able to slow or stop disease progression from either an intensive exercise program or treatment with the drug phenylbutyrate.
How Effective are Mesenchymal Stem Cell Therapies for Age-Related Joint Issues?
Arguably the most robust and reliable of currently available stem cell therapies, though still varying widely in outcome between sources of cell, methods of delivery, and patients, judging by the studies conducted to date, are those involving mesenchymal stem cells. They are now widely used for all sorts of musculoskeletal and joint issues that might benefit from less inflammation and more regeneration. The transplanted cells typically don't live for long, but they do generate signals that produce a sizable temporary change in the local environment, including suppression of chronic inflammation.
It is an interesting question as to the degree to which the observed results of modestly enhanced regeneration following mesenchymal stem cell therapy are secondary to reduced inflammation, versus being caused by pro-regenerative signaling that doesn't relate to inflammation. It is becoming clear that chronic inflammation degrades the normal processes of regeneration and tissue maintenance, all of which involve an intricate dance of stem cells, immune cells, and various other cell populations specific to each tissue type. When immune cell behavior is running off the rails because of constant inflammatory signaling, regeneration is diminished.
Here, I'll point out a small open access study on the use of mesenchymal stem cell therapy for the common age-related joint issue of osteoarthritis, in which cartilage and bone break down. It differs from most earlier studies in tracking patient outcomes for a longer period of time following the procedure, something that is probably needed in order to provide a more definitive answer as to which of the various methodologies of treatment are effective. Osteoarthritis is an inflammatory condition, though the inflammation is localized to the problem joints. Given the results from recent studies, it is beginning to look likely that senescent cells are the major cause of this condition. Since these errant cells are known to generate a potent mix of inflammatory signaling, this all fits together quite nicely.
Mesenchymal stem cell therapies don't address the cause of the issue, but they do appear to damp down inflammation and perhaps issue other regenerative signals for long enough to allow tissues to accomplish some repair of the structural damage despite the presence of senescent cells. It will be interesting to see how senolytic therapies to remove senescent cells compare, as that should provide a good answer to the question above regarding the split of benefits between reduced inflammation versus increased regenerative signaling.
Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study
Knee osteoarthritis (KOA) is a common condition affecting the adult population causing pain and dysfunction of the knee joint. Subsequently, there is a negative impact on the quality of life of these patients. A recent meta-analysis of the 11 trials with 558 patients using mesenchymal stem cells (MSCs) was published. There was an improvement in various clinical scores. The authors concluded that there was no significant difference in the comprehensive evaluation index after stem cell treatment, despite the significant improvement in clinical symptoms and cartilage morphology. A recent phase I-II of expanded autologous bone marrow stem cells has been published. It reported the safety and effectiveness of this modality. There is one published work using allogeneic bone marrow-derived MSCs in advanced KOA in humans showing clinical improvement but no significant MRI improvement.
In this paper, we report on the results of 13 patients who were treated by expanded autologous bone marrow mesenchymal stem cells (BM-MSCs) in an open-label phase I prospective study and followed for 2 years for any adverse events and for efficacy by normalized Knee Osteoarthritis Outcome Score (KOOS) and by MRI.
Knee cartilage has limited regenerative capacity. Mesenchymal stem cells (MSCs) are known to have paracrine and differentiation properties. They can produce extracellular matrix within the joint. These properties make them good target for use in the regeneration of knee cartilage. Whether MSCs stimulate the proliferation and differentiation of resident progenitor cells or they differentiate into chondrocytes remains to be clarified. Rabbit and goat models of osteoarthrosis suggest that the repair occurs through paracrine effects by stimulation of endogenous repair mechanisms.
This work shows that the use of BM-MSCs is safe with only minimal early pain in some patients in the injected joint which resolved quickly without any intermediate or long-term clinical or biochemical adverse events. Bone marrow is attractive since it can easily be harvested as an outpatient procedure and without the need for patient hospitalization. Patients were followed up for 2 years. The work provides preliminary evidence that BM-MSCs are effective in KOA, as judged by the significant improvement in KOOS and by MRI. Mean knee cartilage thickness measured by MRI improved significantly. All symptoms significantly improved conferring significant improvement in the quality of life of these patients with grade II and III KOA. However, we wish to emphasize that the small number of participants in this study prohibits generalization of efficacy, and further work is warranted.
We suggest that next trials should also explore the dose of MSC and the source of MSC. There is a need to establish the safety of allogeneic MSC for KOA. The use of allogenic MSC can be standardized and the dose can be better controlled, and the cell variability can be reduced to the minimum. We believe that MSCs are potential definitive therapy for KOA.
A Look Back at the Science of Longevity and Advocacy for Rejuvenation in 2017
Another year is over, and we're all that much closer to both the ugly declines of aging and the advent of rejuvenation therapies. For those fortunate enough to be in a younger demographic, which of those two items wins out depends entirely on the pace of progress. We are in a race. The results matter greatly. Every effort made to help will shift the odds to be that much better.
A Year of Ups and Downs in Fundraising
Insofar as fundraising goes, this has been a mixed, interesting year of ups and downs. On the one hand it has been a struggle to raise funding for smaller non-profit projects, such as the MouseAge and AgeMeter initiatives at Lifespan.io. At the same time companies working on rejuvenation biotechnology have obtained angel and venture investments, and new venture funds are entering the longevity science community. Ichor Therapeutics announced a series A for their SENS-based Lysoclear technology, and later in the year their other spin-off Antoxerene was funded. Oisin Biotechnologies expanded their technology to target cancerous as well as senescent cells, and are also raising more funding. Other companies involved in senescent cell clearance have done well; SIWA Therapeutics pulled in new funding for their antibody approach, for example, and CellAge was seed funded to work on better assays for senescence. Unity Biotechnology continues to have enough of a war chest to buy the rest of the nascent industry should they so choose. AgeX Therapeutics launched, with Aubrey de Grey on their staff - that should be interesting. LIfT Biosciences seems to be doing well in their efforts to bring leukocyte transfer therapies for cancer to the clinic.
On the other side of the fundraising fence, the Methuselah Fund launched this year, taking a mixed non-profit/for-profit approach, and from the funds raised from our community invested in Leucadia Therapeutics, supporting a new approach to clearing aggregates that cause neurodegeneration. Larger monied interests arrived in the form of Jim Mellon's Juvenescence venture, who have initially invested in Insilico Medicine, but have indicated support for the SENS research agenda. As this is a vocal group, we can expect to see them influencing public and investor opinion rejuvenation research and development in the years ahead.
Despite all of the challenges faced by non-profit fundraisers over the course of much of 2017, the year ended on a high point: the SENS Research Foundation year end fundraiser pulled in 1 million more than the target of 325,000 or so in pledges, as the anonymous principal of the Pineapple Fund donated 1 million in bitcoins in December. The Fight Aging! SENS Patron component of that year-end fundraiser came to a successful conclusion: Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! put up a 36,000 challenge fund to match the next year of monthly donations, and that target was reached. Many thanks are due to all who supported SENS rejuvenation research over the course of the year: this funding makes a real difference, especially now that multiple lines of research are closing on the point at which commercial development can begin. You might take a look at the SENS Research Foundation annual reports and the state of progress in SENS addition to the Fight Aging! FAQ for a sense of how things are going.
Finally, with all of the hype surrounding blockchain initiatives this past year, it was inevitable that some of the adventurous souls in our community would make the effort to run initial coin offerings and see whether or not this was a viable path to pull in funding. The Open Longevity organization set out to give it a try, and so did Youthereum. It is a little early to say where this will all go; it is a very rapidly changing area of effort.
Expanding Efforts in Advocacy
Discussion of advocacy for the cause is a usual feature of our community, as we try things and attempt to make progress in persuading the world that rejuvenation research is plausible, practical, and necessary. There are more people engaged in advocacy now than at any time in the past decade, and so discussions of strategy come up often. New ventures kicked off in 2017 include the Geroscience online magazine, and among the existing ventures the LEAF / Lifespan.io volunteers seem to be hitting their stride. The mainstream media continues to be as much a hindrance as a help, and where it is a help you will usually find Aubrey de Grey involved in the article somewhere - which is not to mention the recent /r/futurology AMA.
In the broader question of strategy in advocacy, questions abound. Do we continue to spend a lot of time tearing down arguments against treating aging as a medical condition, such as the naturalistic fallacy and unfounded fears of overpopulation? Should we be avoiding talk of immortality and radical life extension? Or focusing on ethical arguments? Or correcting mistaken views of aging and the underlying biology? Trying harder to persuade people that rejuvenation therapies are a near future possibility? Or trying to address some of the unhelpful behavior from some members of the research community? Or continuing to hammer on the costs of failing to address aging, the worldwide toll of death and suffering? Or continue to hammer on the benefits of success? Do we talk less and strive to engage with structural problems in the funding of research? Or endeavor to find more funding for advocacy rather than sending it all to research? Given the fact that we have to keep making the same arguments for incremental gains, are we bad at this advocacy business, or is it a tough challenge? Should we switch some of this non-profit activity to for-profit activity?
We must keep making the case, of course - the benefits of success are enormous. There were some sizable wins in advocacy this year, such as a series of YouTube videos from popular channels that covered the prospects for the treatment of aging and were viewed by hundreds of thousands of people.
Topics in Longevity Science from the Past Year
Is genetics important in longevity? Some researchers think that most of the observed variation in human life span is chance, not genes. There has been plenty of other research this year on human genetics that are related to longevity, and there are a number of large commercial ventures working in the space, but it is going to be hard to top the discovery of human PAI-1 mutants who appear to enjoy a seven year gain in life expectancy. Since this mutation is closely connected to cellular senescence, it seems plausible that we should read this as support for the benefits of senolytic therapies. A similar discovery was made for a growth hormone variant, with a much smaller effect, of course. That aside, analysis of genetics doesn't look like a fast road to sizable results for a variety of good reasons.
Cellular senescence research continues apace, of course, alongside the commercial efforts to bring senolytic therapies to the clinic. The research community has now well and truly woken up on this topic, and many researchers are increasingly optimistic that senolytic treatments will be transformative for medicine. New work now implicates cellular senescence in kidney disease, macular degeneration, osteoarthritis, cardiac hypertrophy, sarcopenia, lung diseases, vascular calcification, immune system aging, fibrotic diseases, fatty liver disease, skin aging, declining regenerative capacity, the accelerated aging effect of chemotherapy, the effects of visceral fat on health, and more.
Some groups are trying to find ways to reverse senescence, sabotage harmful signaling by senescent cells, or prevent cells from entering this state - though it is unclear as to whether or not these classes of approach will be significantly helpful, given that the cells are damaged. The more direct and definitively effective approach of destroying senescent cells continues to gather more potential methods. This past year, the very intriguing method involving FOXO4-DRI was demonstrated in mice - we can hope it holds up in human studies, as this looks considerably better than the current crop of repurposed chemotherapeutic senolytic pharmaceuticals. Those chemotherapeutics expanded to include HSP90 inhibitors quite recently. Meanwhile exploration continues in search of better ways to assess the number of senescent cells in tissues; current approaches just aren't all that useful for human clinical applications.
Beyond clearance of senescent cells, other lines of SENS research are progressing. This year, glucospane research turned to the creation of monoclonal antibodies to aid in building a therapy to break cross-links in aged tissues. Gensight continues to find success in their implementation of allotopic expression of mitochondrial genes, proving out the technology platform that will ultimately become a rejuvenation therapy.
Given the advanced state of senolytics, it is only natural that our community is starting to think about trials and how to run them - in addition to whatever the various companies in the space might put together over the next couple of years. Paid trials are a good idea, but there is an unaccountable amount of hostility towards them from the scientific community. Groups such as Betterhumans and the Society for the Rescue of Our Elders are running small, independent senolytic pilot studies. Responsible self-experimentation is another time-honored way forward. Some people are trying it for senolytic treatments. I have put some thought into the logistics and what tests one might use in order to determine whether or not a particular treatment is useful.
Self-experimentation in the broader community nowadays extends to comparatively crude gene therapies, with a number of organizations offering the tools or running the trials. These technologies are too cheap and too easily used to be more than inconvenienced by regulators. A few companies are headed in the same direction, such as Libella Gene Therapeutics, with a plan for human telomerase gene therapy trials, following in BioViva's footsteps.
Lines of research emerging from parabiosis studies, in which old and young individuals have their circulatory systems linked, continue to expand. The core questions regarding whether beneficial factors in young blood or harmful factors in old blood are responsible for the observed effects on aging, or both and to what degree, continue to be debated. While the weight of evidence leans towards "bad old blood" with a few specific candiates for the factors causing that effect, it is still the case that new studies with evidence for beneficial factors in young blood continue to arrive. The contradictions will eventually be resolved, but for now it is an area of research in flux. Meanwhile, human trials of plasma transfusion from young to old continue; Ambrosia and Alkahest reported results that are ambiguous enough to resolve nothing.
Cryonics remains an important and underappreciated technology. Not all of us are going to make it; the progression of rejuvenation technology won't happen fast enough. We will need the backup plan of cryonics. This year marks the fiftieth anniversary of the first, comparatively crude cryopreservation, and that individual, unlike most of those from of that era, remains preserved. The technologies of preservation today are far more advanced, and the organizations more reliable in the face of various failure modes, as noted in an interview from earlier in the year. One line of work that has made considerable progress of late is safe and rapid thawing of vitrified tissues. In community news, the International Longevity and Cryopreservation Summit took place in Spain earlier this year.
Is Google's large investment in aging research, the California Life Company, Calico, at all relevant to the goal of defeating aging? The more we find out, the less likely it appears. Researchers are increasingly willing to go on record as saying that the efforts funded there are just not helpful in the near term. Calico looks like pure curiosity-driven scientific research into understanding the very fine details of aging, which is not what we need at this stage in order to push forward to the range of effective therapies that can be built in the near future.
Amyloid accumulation is one of the causes of aging, and transthyretin amyloid is one of the types of amyloid with more research interest. It is connected to heart disease and osteoarthritis, and may be the majority cause of death in supercentenarians. Covalent Bioscience is one of the companies looking at ways to remove this amyloid. A variety of new research was published this past year, including a better approach to assessing the amount of amyloid present, and RNA inteference and antibody based therapies.
On the topic of biomarkers of aging, there are many various lines of work taking shape. The research community agrees that having effective, reliable biomarkers for a rapid assessment of biological age is very necessary to speed up progress towards treatments for aging. Among efforts noted this year include gene expression of glia, metrics based on neuroimaging, or on microRNA expression, various attempts to assemble a compound biomarker from a collection of standard lab tests and measures. People are setting up online databases to hold the various prospects. DNA methylation tests based on one or more of the existing epigenetic clocks have now reached the consumer marketplace. They can be ordered from Osiris Green and Zymo Research. The research community continues to refine and expand further epigenetic clocks and related assessments.
Calorie restriction is ever a popular research topic, despite this being unlikely to produce very large effects on human lifespan. This is really the core of the geroscience view of the treatment of aging: slow it down a bit, but don't try for more. Researchers now claim that human studies show a slowing of aging via a collection of biomarkers. The final consensus on long-running primate studies appears to be that, yes, calorie restriction does modestly slow aging in our near relatives. Near all specific measures of aging are similarly slowed, such as the fibrosis leading to kidney disease, the early stages of cancer, the epigenetic changes of aging, the decline of the immune system, the accumulation of metabolic waste in cells, and the accumulation of amyloid in aged tissues. Researchers continue to find new mechanisms by which calorie restriction produces its effects, such as a slowing of ribosomal activity. Sense of smell continues to surprise the research community in the degree to which it is important in determining response to calorie intake. A number of researchers have gained traction in pushing forward intermittent fasting as an alternative approach, particularly the fasting mimicking diet. Meanwhile, ever more candidate drugs and protein targets are found that might act as a basis for potential calorie restriction mimetic therapies - though given the lack of concrete progress on this front over the past decade, I wouldn't hold my breath waiting for results.
Another rising topic in aging research is the contribution of gut microbes and other microbial populations in the body; these may be as influential over aging as, say, exercise or calorie intake. Researchers have noted influences on amyloid accumulation, something that is attracing greater interest from the Alzheimer's research community. It is also interesting to see studies demonstrating extended life as a result of transplantion of gut bacteria from young animals to old animals in zebrafish and in mice, or showing that healthier older individuals have microbial populations more like those of younger individuals. Moving beyond observations, candidate mechanisms are being discovered to explain exactly why changes in gut bacteria are good or bad. The next step is therapies that target those mechanisms. Researchers appear close to being able to sabotage the detrimental effects of oral bacteria, for example.
A few interesting views on aging and its origins surfaced in the past year: aging as a consequence of complexity in cellular life, for example, or that aging is an inevitable consequence of competition between cell types in multicellular life. Another group argued for selection to decline with age even in hypothetical immortals, thus ensuring that no species would become so exceptionally long lived. Others have looked for explanations for the present state of stem cell populations, in that they are not as effective as they could be, especially in later life.
Work on addressing dysfunction in the immune system by destroying near all immune cells and then repopulating them via cell therapy, shown to cure severe autoimmune disease is progressing on a number of fronts. The most important thing here is to find a safer, less damaging way to kill the unwanted parts of the immune system. Currently it is too risky to be applied to older people, so as to clear out the issues in an aged immune system. Researchers recently discovered a promising lead here.
Regenerative medicine, cell therapies, and tissue engineering are energetic fields. Far too much is going on to note all of it, but a few things caught my eye. The Methuselah Foundation continues to be in the thick of it with their initiatives to promote progress, for example. Decellularization continues to be an important line of research, and that will be the case until someone figures out a reliable means of producing blood vessel networks. Bioprinting of tissue proceeds apace, and is driving a lot of the advances in reduced cost and increased capabilities. Researchers are building ever more and better organoids: fully functional ovaries, stomach, skin that is fully and completely structured, lungs, thymus, bile ducts, inner ear, and more. Organoid production is on the verge of scaling up, and use of multiple organoids may work well as an alternative to full organ transplant for some organs. In other parts of the tissue engineering field, mass production is also an ongoing interest. Organ factories are not so very far ahead. Teeth are similarly moving forward; tooth regrowth has moved up from rodents to canines. Researchers are also making inroads into the manufacture of blood to order.
Will regenerative medicine make the leap soon from cell therapies that do little but suppress inflammation, to actual methods of rejuvenation and repair? That is hard to say, and the final form of such therapies is also uncertain. Consider induced cell turnover or artificially increased cell replication strategies for example, a novel approach where the implications have yet to be fully explored, or the variety of cell therapies that appear to produce quite sizable changes despite using only incremental advances in methodology, or very novel processes such as reprogramming skin cells into stem cells in a living individual. Comparative biology continues to deliver intriguing findings from lizards, spiny mice, zebrafish, and the like. Related work is finding that adjusting the balance between populations of macrophages with different polarizations can spur greater regeneration in mammals, and the same may be true of microglia.
2017 Short Essays
You'll find a number of short essays at Fight Aging! each year. Here is a selection from 2017:
- Why Rejuvenation Research Startups Go Quiet Following Launch
- Will Senescent Cell Clearance Therapies Sink the Pensions and Annuities Industry?
- The Million Year Life Span
- If Much Older than 30, Save More Aggressively Over the Next Decade or Two
- What Next for Unity Biotechnology?
- The Problem with Focusing on Healthspan
- Advocacy for Rejuvenation Research is as Much a Process of Documentation as it is a Process of Persuasion
- The Fall into Nihilism
- Success in Rejuvenation Research to Date is Partial: Many Projects Still Need Our Philanthropic Support to Flourish
- Wolf has been Cried So Very Many Times When it Comes to Anti-Aging Therapies
- Patient Paid Clinical Studies are a Good Plan for Rejuvenation Therapies
Looking Ahead to 2018
Next year should see the first published results from senolytic trials - and if the effects of the first drug candidates translate well from mice to humans, that should wake up everyone not yet aware of the enormous potential of this field. I expect that this will probably overshadow everything else achieved in the field for a while, at least in the public eye. There will be more startup companies launched to work on SENS rejuvenation biotechnologies, and that will hopefully be an ongoing story for the next few years. This period of transition, handing off from laboratory to clinical development, is critical to the future of human rejuvenation therapies. The more we can do to help, the better.
An Interview with Aubrey de Grey, Focused on the Science of Rejuvenation Therapies
Aubrey de Grey of the SENS Research Foundation needs little introduction to the audience here. His efforts and those of his allies have gone a long way towards ensuring that we will benefit from the first generation of rejuvenation therapies to emerge over the years ahead. The interviewer here is focused on the science of SENS, the Strategies for Engineered Negligible Senescence, a recipe for the control of aging through periodic repair and reversal of its root causes. I encourage you to read the whole interview rather than just the snippets below; it is fairly long.
Feinerman: The past five years have been remarkable. Now every day I read new articles and news about age reversal. I believe we will remember 2016-2017 as the most important years. Do you share this feeling?
de Grey: Yes and no. Yes, in the sense that there are indeed more and more exciting breakthroughs being made in the lab - and of course I am very proud that SENS Research Foundation is responsible for some of them. But no, in the sense that there is still a terribly long way to go; we need to fix a lot of different things in order to get rid of ageing, and for some of them we are still at a very early stage in the research.
Feinerman: Your famous book "Ending Ageing" was published 10 years ago. Would you like to make a new version?
de Grey: I probably should, at some point, but it's not a priority, because the overall approach that we described in that book has stood the test of time: we have made plenty of progress, and we have not come across any unforeseen obstacles that made us change course with regard to any of the types of damage.
Feinerman: You look for bacteria who feed on dead animals to find enzymes capable of breaking glucosepane. How do you find useful bacteria?
de Grey: We are using a "metagenomic" strategy for identifying enzymes that can break glucosepane: we take standard E. coli bacteria, we break one or two of their genes so that they become unable to synthesise one or another chemical (in this case typically arginine or lysine) so that they need to take it up from their surroundings. Then we add random DNA from the environment, which could come from any bacteria, even unculturable ones, and add bits of it to the E. coli. Very occasionally the new DNA may encode an enzyme that breaks glucosepane, and if so, the bacteria will grow even without any arginine or lysine in the environment, if (but only if) we give them glucosepane instead and they break it to create arginine and lysine.
Feinerman: In your book you proposed Whole-body Interdiction of Lengthening of Telomeres (WILT) - the removal of telomerase in all cells in order to prevent cancer and reseeding stem cell populations regularly. Has there been any success in that?
de Grey: We are making progress there, yes; in particular we have shown that telomerase-negative stem cell reseeding works for the blood. However, no, the problem with non-integrating telomerase is that it will extend cancer telomeres just as much as normal cells' telomeres. I support that research, though, not least because there may be breakthroughs in combating cancer in other ways (especially with the immune system), in which case it would be much safer to stimulate telomerase systemically.
Feinerman: Now we have very precise CRISPR, and removing genes is easier than inserting ones because you can target the same cell more than once. When we solve delivery problems will we be able to apply WILT?
de Grey: Yes, certainly.
Feinerman: Why can't we remove telomerase locally in compromised tissue?
de Grey: It's being tried, but it is very difficult to make the removal selective.
Feinerman: There is growing evidence that epigenetic changes are highly organized and may be one of the causes of ageing. What do you think? Maybe should we consider epigenetic changes as another type of damage in SENS model, calling EpiSENS?
de Grey: We need to be much more precise with definitions in order to answer your question. Epigenetic changes can be classified into two main classes: shift and noise. Shift means changes that occur in a coordinated manner among all cells of a given type and tissue, whereas noise means changes that occur in some such cells but not others, increasing the variability of that type of cell. Shifts are caused by some sort of program (genetic changes to the cell's environment), so yes, they can potentially be reversed by restoring the environment and putting the program into reverse. Noise, on the other hand, is not reversible. And we have for several years worked on determining whether it happens enough to matter in a currently normal lifetime. We have not got to a definitive answer, but it's looking though no, epigenetic noise accumulates too slowly to matter, other than maybe for cancer (which, of course, we are addressing in other ways).
Feinerman: Should we use reprogramming factors to reverse the epigenetic program?
de Grey: Probably not. There may be some benefits in doing so, as a way to restore the numbers of certain types of stem cells, but we can always do that by other methods (especially by direct stem cell transplantation), so I don't think we will ever actually need to dedifferentiate cells in vivo.
Feinerman: What do you think of the idea of Whole-body Induced Cell Turnover (WICT)?
de Grey: The general idea of accelerating cell turnover is definitely a good one. It is a bit like the idea of replacing whole organs: if you replace the entire structure, you don't need to repair the damage that the structure contains. However, also like replacement of organs, it has potential downsides, because evolution has give us a particular rate of turnover of particular cells, and the function of each of our cell types is optimised for that. So it may end up being complicated, with many pros and cons.
Feinerman: Won't it be easier to print or grow new organs instead of rejuvenating the old ones?
de Grey: That's absolutely correct. I expect that in the early days of implementing SENS, some organs will be easier to replace than to repair. However, of course replacing an organ requires invasive surgery, so we will want to develop repair eventually.
Feinerman: What in your opinion will be the order of arrival of rejuvenating therapies?
de Grey: Well, a lot of the stem cell side of things is in clinical trials already, and removal of amyloid is there too in the case of Alzheimer's. Next on the list will probably be senescent cell ablation, which Unity Biotechnology are saying will be in the clinic next year, and removal of intracellular garbage for macular degeneration will also be, courtesy of our spinout Ichor Therapeutics. The other three are harder but they are all chugging along!
Feinerman: There are about twenty various types of amyloids, we can see some success in removing transthyretin and beta-amyloid. What is about others? Can we scale success in removing the above two on the others?
de Grey: I'm very confident that the removal of other amyloids can be achieved using more or less the same methods that have worked against those two. The next one on my list would be islet amyloid, which contributes to diabetes.
Feinerman: When I ask people to donate to SENS Research Foundation they often say that their a few bucks don't matter. What can you say to our readers to encourage them?
de Grey: One way to say it is to calculate how much it would take to save a life by donating to SENS. I estimate that a budget of 50 million per year would let us go three times faster than now and would bring forward the defeat of ageing by about a decade. About 400 million people die of ageing in a decade, so that means donating to SENS has a bang-for-the-buck that no other cause comes anywhere near.
An Illustration of the Cost of Aging on Individual Health and Survival
The field of aging research could do with more of its scientists choosing to write for laypeople; the more outreach the better. This short column by researcher Steven Austad illustrates one way of looking at aging - that it is all about the mortality rate at a given age, and the inexorable rise of that mortality rate over time, caused by the accumulation of cell and tissue damage. By this metric an individual at age 40 or 50 is already significantly impacted by the processes of aging in comparison with an individual at age 20, manifesting as an increased mortality rate. Given this, there is every chance that a half-way decent first generation rejuvenation therapy would be of some benefit to people at age 40, those the medical establishment currently designates as being in perfect health, but who nonetheless have a mortality rate that is considerably higher than is the case for people at age 20.
I have a pill. If you decide to take my pill, you immediately stop aging and are preserved in your current physical state from this day forward. This hypothetical pill that stops aging, call it the Methuselah pill, will not make you immortal. Immortality does not exist in this world. Whether or not you age, you can still step in front of a bus, eat a contaminated hamburger, catch a stray bullet, or be struck by lightning. In fact, if you lived long enough one of these things would almost be guaranteed to happen to you.
One way that scientists define aging is that it increases the chance that you will die in the coming year. In America, your chance of dying doubles every 8 years after about age 35. But with the Methuselah pill that no longer happens. You have the same chance of dying, you look the same, you feel the same, as the age at which you took the pill, forever. Would you want to be frozen in time with the physical looks, the energy, strength and agility you had when you were 20? Give this some careful thought because half of you - the male half - may remember 20 as the testosterone-soaked age at which you were more than a little crazy. Maybe you'd like to be preserved at age 50, when people will take you more seriously. You would be more settled in life, a bit more thoughtful, a bit less swift.
One thing to consider. The age you choose to stop aging has a great deal to do with how much longer you can expect to live. A little simple algebra with U.S. government statistics shows that with a 20 year old male survival rate lasting into infinity, your life expectancy is another 600 years rather than the 57 years it is in reality. Not a bad bargain for staying a little crazy. If you're a woman, you're not so crazy at that age and you are also better designed for survival than your male counterparts. That's a sad fact of biology, men. You could expect to survive another 1700 years rather than 62 years you can expect in reality, nearly three times as long as those crazy men. I know it doesn't sound fair, fellows, but age 20 is when the survival advantage of women over men is close to its greatest.
If you decided to stop aging when you are a dignified and mature 50 year-old, you will have sacrificed a lot of future years to achieve that dignified look. Fifty year olds are about 6 times more likely to die in a given year than 20 year olds. Not only that, but you could expect to live with some aches and pains that you didn't anticipate. You won't hear as well and will probably be holding the newspaper or your smart phone at arm's length, but at least that testosterone problem will no longer be so pressing. Your life expectancy, however, has dropped to a mere 140 years if you're a man and a little over 200 years if you're a woman. Ladies, that decision to stop aging at 50 rather than 20 has cost you 1500 years of life expectancy and a considerable amount of pain. You suspected it was a bad decision, didn't you?
The point of this exercise, I suppose, besides having a little fun and stimulating a little thought is to give readers a visceral feel for the toll that aging exacts on us. Back here in the real world, there has been only one confirmed 120 year old person, a woman naturally, in the history of our species. No one yet has approached even 130 years, although some of us researchers are working to change that.
Mapranosis: the Influence of Commensal Microbes on Neurodegenerative Disease
Commensal microbes are the largely helpful populations that live inside us, usually meaning the gut microbiota, but there are others, such as the bacteria found in the mouth. Among these largely helpful microbes are a range of species that cause us harm over the years, however - consider the bacterial origins of gum disease, for example. Researchers are increasingly interested in the ways in which the swarming microbial life inside us, and particularly in the gut, might influence the progression of aging; to what degree are gut bacteria a cause of the observed natural variations in pace and outcome of aging in mammals? This is an open question.
In the case of neurodegenerative conditions such as Alzheimer's disease, microbial life may contribute by generating some fraction of the amyloid deposits or chronic inflammation known to be associated with the condition. In this context, some scientists are focused on invading microbes such as spirochetes, while others, like those noted here, are more interested in the commensal microbes that normally live inside us. There is a fair amount of evidence for either of these two classes of microbe to be involved.
Research in the past two decades has revealed that microbial organisms in the gut influence health and disease in many ways, particularly related to immune function, metabolism, and resistance to infection. Recent studies have shown that gut microbes also may cause or worsen Parkinson's disease, Alzheimer's disease and other neurodegenerative conditions. Researchers now propose the term "mapranosis" for the process by which amyloid proteins produced by microbes (bacteria, fungi and others) alter the structure of proteins (proteopathy) and enhance inflammation in the nervous system, thereby initiating or augmenting brain disease. The term is derived from Microbiota Associated Protepathy And Neuroinflammation + osis (a process).
Research into the multitude of microbes that inhabit the human body has expanded considerably in recent years. Genomic analysis has begun to reveal the full diversity of bacteria, viruses, fungi, archaea, and parasites living in and on the body, the majority of them in the gut. Even more recently, researchers have begun to explore how the proteins and other metabolites produced by microbes inhabiting the gut influence functions in other parts of the body, including the brain. However, we do not yet have a full understanding of how these systems work. The relationship between the microbiota and the brain has been called the "gut-brain axis."
It is understood that the clumping of misfolded amyloid proteins, structures produced by neurons in the brain, are associated with neurodegeneration and conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). "It is well known that patterns of amyloid misfolding of neuronal proteins are involved in age-related brain diseases. Recent studies suggest that similar protein structures produced by gut bacteria, referred to as bacterial amyloid, may be involved in the initiation of neurodegenerative processes in the brain. Bacterial amyloids are produced by a wide range of microbes that inhabit the GI tract, including the mouth. Our work suggests that our commensal microbial partners make functional extracellular amyloid proteins, which interact with host proteins through cross-seeding of amyloid misfolding and trigger neuroinflammation in the brain."
Summarizing the Current Understanding of Immunosenescence
The open access review paper here provides a summary of the present scientific understanding of immunosenescence, the name given to the declining function of the immune system with advancing age. Some researchers consider this a separate phenomenon from inflammaging, the increased levels of inappropriate inflammatory activation of the immune system found in older individuals, and also distinct from some other kinds of immune cell failure found in old people, such as cellular senescence or immune cell exhaustion. Others consider all of these line items to be aspects of immunosenescence. Further, when it comes to the roots of age-related immune failure, the degree to which various potential causes are responsible is open to debate, and there will likely remain considerable uncertainty until such time as the research community can reverse those causes one by one to observe the results.
In our era of rapidly improving biotechnology, it is frequently the case that building therapies to address the causes of age-related dysfunction is the fastest path to an understanding of which of those causes are important. In the case of immunosenescence, there are a number of obvious paths forward, some of which should also help to treat autoimmune conditions: reversing atrophy of the thymus to increase the supply of new immune cells; destroying damaged or overspecialized immune cells to free up space for effective replacements; using cell therapies to deliver a large number of new immune cells; restoring function of the hematopoietic stem cells that generate immune cells.
Immunosenescence correlates with the linear extension of average life span that began in the nineteenth century and is still in progress. The aging phenotype, including immunosenescence, is the result of an imbalance between inflammatory and anti-inflammatory mechanisms with the consequence of a state defined by some authors as inflammaging. The most important feature of immunosenescence is the accumulation in the "immunological space" of memory and effector cells as a result of the stimulation caused by repeated clinical and subclinical infections and by continuous exposure to antigens. This state of chronic inflammation that characterizes senescence has a significant impact on survival and fragility. In fact, the condition of frail elderly occurs less frequently in situations characterized by low contact with viral infections and parasitic diseases. Furthermore immunosenescence is characterized by a particular remodelling of the immune system, induced by oxidative stress.
Apoptosis, a complex mechanism of programmed cell death, allows the maintenance of a physiological homeostasis mechanisms between survival and removal of damaged cells. Apoptosis is a strategic mechanism for the manifestation of the clonotypic diversity during lymphocyte selection, permitting to control the clonal expansion after antigenic stimulation. Changes in apoptosis, together with inflammaging and the up-regulation of the immune response with the consequent secretion of pro-inflammatory lymphokines, represents the major determinant of the rate of aging and longevity, as well as of the most common diseases related with age and with tumors. Other changes occur in innate immunity, the first line of defence providing rapid, but unspecific and incomplete protection, consisting mostly of monocytes, natural killer cells, and dendritic cells, acting up to the establishment of an adaptive immune response, which is slower, but highly specific, which cellular substrate consists of T and B lymphocytes.
The markers of inflammaging in adaptive immunity in centenarians are characterized by a decrease in naive T cells. The reduction of CD8- cells may be related to the risk of morbidity and death, as well as the combination of the increase of CD8+ cells and reduction of CD4+ T cells and the reduction of CD19+ B cells. The immune function of the elderly is weakened to due to the exhaustion of CD95 T cells, which are replaced with the clonal expansion of CD28- T cells. The increase of pro-inflammatory cytokines is associated with dementia, Parkinson's disease, atherosclerosis, type 2 diabetes, sarcopenia, and a high risk of morbidity and mortality. A correct modulation of immune responses and apoptotic phenomena can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases.
Reduced FOXO3 in Lung Fibrosis Points to Cellular Senescence
Researchers have found that fibrosis in the lung can be controlled via levels of FOXO3. This dovetails nicely with recent evidence for increased levels of cellular senescence to be a cause of lung fibrosis, as loss of FOXO3 triggers greater senescence in cell populations. This relationship might explain the observed associations of FOXO3 with longevity, though these are not as large as one might expect if it did have a strong effect on senescence. Other FOXO proteins also play a role in the determination of senescence versus self-destruction in cells that are damaged or have reached the end of their replicative life span, as demonstrated by the use of FOXO4-DRI as a senolytic compound that can trigger senescent cell apoptosis. All of this is interesting, but probably somewhat secondary to the goal of destroying senescent cells - it seems likely that FOXO3 is either moderating the bad behavior of senescent cells, preventing their influence from generating fibrosis, or perhaps preventing new cells from becoming senescent without much affecting existing senescent cells.
Idiopathic pulmonary fibrosis is currently an incurable lung disease, in which sufferers lose the ability to absorb adequate oxygen. Although the word 'idiopathic' means that the cause is unknown, the disease primarily affects former and active heavy smokers from the age of 50. An important role in idiopathic pulmonary fibrosis is played by connective tissue cells called fibroblasts. These cells provide structure to the air sacs (alveoli) in the lungs. During development of the disease, characteristic changes to these fibroblasts are observed. "The fibroblasts undergo a kind of personality change. In patients with pulmonary fibrosis, these cells contain increased amounts of contractile proteins, like those involved in muscle cell function." These modified cells, known as myofibroblasts, are responsible for the changes in connective tissue structure. As the disease progresses, the air sacs increasingly degenerate, resulting in damage to the blood vessels in the lungs. This results in shortness of breath.
Researchers decided to look for a factor which might be responsible for the fibroblast changes. Such a factor could hold the key to a possible treatment. The team first compared connective tissue cells from healthy individuals and patients with pulmonary fibrosis. "We noticed a transcription factor called FoxO3. Cells from patients with pulmonary fibrosis contained less of this protein than cells from healthy controls. The results were even clearer once we looked at FoxO3 activity - it was much lower in fibroblasts from patients with pulmonary fibrosis than in cells from healthy people." The researchers then turned their attention to animal research and develped a mouse model of the disease. They found that mice with pulmonary fibrosis also had reduced FoxO3 activity. The effect was much greater in mice which had been genetically modified to lack FoxO3.
Reactivating FoxO3 in patients with pulmonary fibrosis might, therefore, offer a way of treating the disease. This approach proved successful in mice: treating mice with pulmonary fibrosis with UCN-01 resulted in a reduction in symptoms and improved lung function. This effect was not observed in mice that lacked FoxO3. UCN-01 is a substance which activates FoxO3 and is currently undergoing clinical trials as a tumour therapy. Further studies will examine this link more closely, in the hope of eventually being able to start trials on patients.
BioViva Illustrates the Tension Between Progress and Regulation
Elizabeth Parrish of BioViva, you might recall, has made every effort to publicize the follistatin and telomerase gene therapy that she underwent. This is a strategy intended to accelerate progress; I suspect she was not the first, and that others were just more circumspect. The technology exists, it is not expensive in the grand scheme of things, and at the very least hundreds of people have the laboratory access and the knowledge to carry out such an operation. BioViva's efforts, and those of other ventures such as the Odin and Ascendance Biomedical illustrate the tension between desire for progress and desire for regulation. As a general rule, the majority of people who are not suffering significantly at the present time are just fine with heavy-handed regulation that holds back progress towards cures and enhancements. The minority of people who are suffering want the option to undergo treatments that they have researched and chosen, that appear to have a good chance of working, but are not going to be approved by regulators in the foreseeable future. Unfortunately they are largely ignored by the powers that be, and vitriol is heaped upon anyone who flouts medical regulation.
You can see how this plays out against a backdrop of technological progress by looking at the history of stem cell therapies. The primary goal of regulators is to avoid poor publicity, and they achieve this by putting as many roadblocks as possible in the way of new medical technology. Blocking new technologies causes a lot less bad publicity than is the case when something that causes harm slips though. Since medicine is uncertain and conditional, near every useful medical technology can, in some context, cause harm - or appear to cause harm in a naive view of the circumstances - so regulators become strongly biased against any form of progress.
Look at how costs of FDA approval have doubled in the past decade - ever more is required of petitioners in the effort to reduce bad publicity for regulators by any and all means possible. The media is ever ready to broadcast any failure in medicine, but generally reluctant to talk about the very real cost of suppressing progress in medical technology. Regulators will continue to hold back new technologies until the widespread availability of said technologies in other regions makes them look like clowns for doing so. This is exactly what happened for first generation stem cell therapies, and is exactly what will happen for gene therapy technologies. Making new medicines available via experimentation and medical tourism is the only reliable path forward to faster general availability.
Elizabeth Parrish is a proponent of controversial ideas. Rankled by barriers to trials on potential life-enhancing treatments, she used herself as a guinea pig and says the results have borne fruit - but she has irked the science community in the process. The CEO of Seattle-based BioViva, a biotechnology company that focuses on developing gene therapies to slow the ageing process, revealed that in September 2015 she flew to Colombia and tried two experimental gene therapies on herself. Six months later, BioViva claimed the experiment was a success against ageing and that the treatment lowered the biological age of Parrish's immune cells by 20 years.
Parrish's actions caused a stir within the industry, mainly because BioViva had not done the pre-clinical work needed to progress to human studies or testing. Neither did the US Food and Drug Administration authorise Parrish's rogue experiment - hence the trip to Colombia. But Parrish denies her actions were reckless. "As a matter of fact, not intervening in one's health is more reckless because we already know how we'll die. We can actually use this powerful technology to treat many of the diseases of childhood and ageing. We studied a couple of gene therapies that had the most promise to treat not only adult diseases, but also childhood diseases, and I took them to prove they were safe to the world."
Parrish's foray into longevity science began when she stumbled upon a SENS Research Foundation conference in Cambridge, UK, and discovered how gene modifications had extended the normal lifespan of worms and mice. It was there she learned ageing ought to be classified as a disease, a collection of conditions including cancer, heart disease, stroke, and dementia and that everyone will suffer. She wanted to tell the world and get people to put money behind finding a cure. "Ageing is the biggest killer on the planet - by 2050 it will be the biggest killer in every small pocket of the world. To think that ageing is a problem of industrialised countries is just not correct. In countries that are developing right now we see most of the causes of death are associated with ageing - cancer, heart disease and various other things."
Since her personal experiment, Parrish says people have contacted her to ask if they can try her anti-ageing gene therapy. She admits this is not enough to expedite the official sanction for use of such therapies in humans. Instead, she is interested in asking countries to re-regulate. While the "EU has passed through regulations for a couple of gene therapies and the US FDA is following," Parrish wants to set up partnerships with governments, universities and paid-for trials (for those who can afford the hefty price tag). Scientific rigour in Parrish's work is the massive snag in her efforts to peddle gene therapies to the world. Many scientists, including those that are and have been a part of BioViva's scientific advisory board, have told the media that bypassing preclinical studies and trials raises serious ethical questions about how quickly such treatments can be tested on people, and whether medical regulators can be dodged.
Parrish's goal of bringing gene therapies to thousands of people could well be a pipe dream, but her sense of urgency about solving the world's ageing crisis is real. "By 2050 there'll be ten times more people living over the age of 100. It's fantastic news that we're living longer, but we need to live healthy longer. Right now, if you're running a drug through innovation through the US Food and Drug Administration it's 15-plus years and costs at least a billion. It's too slow. We lose 40 million people a year to ageing."
Tissue Engineering of Better, More Correctly Structured Kidney Organoids
The research community continues to improve their ability to build structured and functional organ tissue from the starting point of a patient cell sample. The challenge of constructing blood vessel networks to support large tissue structures remains to be solved, but by the time it is, there will be a direct path to the manufacture of entire organs on demand. Work on kidney tissue is one of the leading areas from the point of view of technical capabilities in tissue engineering, as this research news demonstrates.
In the embryonic kidney, three types of precursor cells, nephron progenitor cells, ureteric buds, and interstitial progenitor cells, interact to form three-dimensional structures of the kidney. Methods to induce nephron structures via nephron progenitor cells from mouse pluripotent stem cells (PSCs) have already been established. However, since other progenitor cells were not included, the "higher-order" structures of the kidney (the state in which differentiated nephron structures are organically connected to each other by branching collecting ducts) were not reproduced. Now, a research group has developed a method of using PSCs to induce production of ureteric buds, the progenitors of branched collecting ducts, and has succeeded in reproducing the higher-order structure of the kidney.
Unfortunately, opportunities for kidney transplantation are limited, but the 2006 discovery of induced pluripotent stem cells (iPS cells) has elevated the expectation for regenerative medicine to "build" fully functioning organs. However, the process of reproducing a whole organ structure continues to be a common and challenging theme for any organ regeneration study. Researchers are working toward the goal of producing a fully functional kidney. To do so, it is important to reconstruct higher-order kidney structures from PSCs.
The researchers first discovered that mouse Wolffian ducts (WDs), precursors of ureteric buds, gradually matured and gained branching capacity between embryogenesis day (E) 8.75 and E11.5. They were then able to culture WD cells in vitro and determined the growth factors necessary to produce mature ureteric buds. Finally, they developed a protocol to induce E11.5 ureteric bud-like cells from mouse ESCs via E8.75 WD-like cells. It was revealed here that nephron progenitor cells and ureteric buds require individually optimized conditions for successful induction.
Functionality of mouse ESC-derived ureteric buds was further verified by co-culturing a single bud with embryonic kidney precursors, or with a mixture of ESC-derived nephron progenitors and embryonic stromal progenitors. In the reconstructed kidney organoid, researchers observed the formation of branching ureteric epithelium, differentiated nephrons, and nephron progenitors on the surface of the ureteric bud tips, thereby confirming the functionality of induced ureteric buds and the reconstruction of higher-order kidney structures. With a slight modification of the protocol, the researchers were able to induce ureteric buds from human iPSCs, and confirmed their branching capacity when cultured with growth factors.
Eotaxin-1 as a Potentially Damaging Factor in Old Blood
Debate continues over the mechanisms responsible for the outcomes observed in parabiosis studies, in which a young and an old individual have their circulatory systems linked. The young individual shows a decline in measures of health, while the old individual shows an improvement - a modest reversal in some aspects of aging. That there must be harmful factors in old blood seems a solid conclusion, but are benefits to the older individual mediated by the presence of beneficial factors in young blood, or by dilution of harmful factors in old blood? There is evidence for both sides. Here, researchers outline some of the support for eotaxin-1 to be one of the harmful factors present in larger amounts in the bloodstream of older individuals, and consider possible implications for the blood transfusion industry.
High blood levels of the chemokine eotaxin-1 (CCL11) have recently been associated with aging and dementia, as well as impaired memory and learning in humans. Importantly, eotaxin-1 was shown to pass the blood-brain-barrier (BBB) and has been identified as crucial mediator of decreased neurogenesis and cognitive impairment in young mice after being surgically connected to the vessel system of old animals in a parabiosis model. It thus has to be assumed that differences in eotaxin-1 levels between blood donors and recipients might influence cognitive functions also in humans. However, it is unknown if eotaxin-1 is stable during processing and storage of transfusion blood components.
In this study, we show for the first time that ready-to-use transfusion blood components contain CCL11 at a physiological concentration. Importantly, in both blood components eotaxin-1 expression did not differ between males and females, but significantly increased with the donor's age in both sexes. Of note, eotaxin-1 levels detected in these processed, transfusible blood products are comparable with those found in unprocessed plasma of healthy individuals. We demonstrated that eotaxin-1 is subject to only minor donor-specific changes over 15 measurements within a 3-months period of time, even when samples have been taken at different times of day. Taken together, our findings and the available literature prove that eotaxin-1 is a relatively stable factor in fresh or processed blood components of one individual over a longer period of time, but significantly rises with increasing age.
Eotaxin-1 was found increased in Alzheimer's disease patients compared to age-matched controls. Eotaxin-1 correlated with impaired verbal and visual memory, and other conditions associated with cognitive decline, such as recurrent depression have also been associated with increased levels of the chemokine. Moreover, it was demonstrated that, among a range of cytokines and chemokines, eotaxin-1 correlated most strongly with reduced hippocampal neurogenesis and aging in mice, and importantly, artificially increasing eotaxin-1 levels in young mice resulted in decreased neurogenesis as well as in impaired memory and learning. Using mouse parabiosis models further proved that exposure of a young animal to the systemic milieu of an older mouse is sufficient to induce severe cognitive impairments and reduced neurogenesis after 2-5 weeks, and identify blood-borne eotaxin-1 as one of the responsible factors.
It has to be considered that a direct impact of short-term eotaxin-1 exposure on neurogenesis and mental factors has only been assessed in mice so far. It is unclear whether a single transfusion of high-eotaxin-1 containing blood components to recipients with very low levels will indeed change total eotaxin-1 levels in the recipient, if this elevation is transient or durable, and if it does indeed influence cognitive functions in humans. Future studies require a prospective study design to carefully resolve these questions.
VCP Discovered to be Important in Cardiac Hypertrophy
Here, researchers investigate the role of the VCP gene in producing cardiac hypertrophy as a response to hypertension, or high blood pressure. Blood vessels become stiff with age, the result of cross-linking, calcification, and dysfunction in the smooth muscle that controls contraction and dilation. This causes hypertension by breaking the finely balanced feedback systems that regulate blood pressure in response to environmental circumstances. Hypertension in turn causes cardiac hypertrophy: heart tissue expands inappropriately to become both larger and weaker. At the end of this road lies death due to heart failure or structural failure of critical blood vessels in a high pressure environment. Addressing the root causes would be the best way forward, but most research groups are more interested in controlling mechanisms at later stages of the process, such as VCP. Therapies based on this sort of work have the potential to produce some benefits, but nowhere near as comprehensively as reversal of vascular stiffness.
Pressure overload-induced cardiac hypertrophy, such as that caused by chronic hypertension, is a major independent risk factor for heart failure. Accumulating evidences from studies in patients and animal models suggest that cardiac hypertrophy induced by chronic pressure overload is not a compensatory but rather a maladaptive process. Despite intensive research efforts over several decades, the molecular mechanisms of hypertrophic heart failure are not fully understood. Therefore, it has become compulsory to identify novel targets involved in the pathogenesis of cardiac hypertrophy and its transition to heart failure.
Our previous studies identified valosin-containing protein (VCP) in the heart and showed that it is a critical mediator of cardiomyocyte survival under ischemic stress both in vitro and in vivo. However, the role of VCP in cardiac growth or hypertrophy under stress conditions was completely unknown. We observed that VCP expression was significantly down-regulated in the hypertrophic left ventricle (LV) tissues of both hypertensive rats and transverse aortic constriction (TAC)-induced pressure-overloaded mice. These findings demonstrated a strong link between down-regulation of VCP expression and hypertensive cardiomyopathy. Reciprocally, cardiac-specific overexpression of VCP in a transgenic (TG) mouse significantly attenuated the pressure overload-induced cardiac hypertrophy. These data together suggested that VCP plays a critical role in pressure overload-induced cardiac hypertrophy.
Direct evidence of VCP's cardioprotective effect was shown in an in vitro study where VCP was downregulated in AngII-induced hypertrophic cardiomyocytes in a dose- and time-dependent manner, whereas the overexpression of VCP prevented AngII-induced cardiomyocyte hypertrophy. In addition, we also found that VCP plays a dual role on the regulation of the mechanistic target of rapamycin (mTOR) signaling in the heart: activating the survival-promoting mTORC2 but repressing the stress-induced growth-promoting mTORC1. These data suggested that VCP acts as a negative regulator of mTORC1 under stress of pressure overload. These selective effects of VCP on mTORC1 and mTORC2 are different from that of other mTOR regulators identified in the heart, such as rapamycin, and also distinct from the function of VCP observed in other tissues. Moreover, VCP suppressed mTORC1 signaling only under the stress of TAC but not at the baseline condition.
Our data collectively concluded that pressure overload reduced VCP expression in the heart which attenuated the inhibitive effect of VCP on mTORC1 signaling, subsequently promoting the pro-growth pathway and resulting in cardiac hypertrophy. These findings bring new insights to the regulatory effects of VCP in the heart and also lead to a new therapeutic target for pressure overload-induced cardiac pathogenesis.
Telomere Length as Presently Measured is Not a Useful Biomarker of Aging
Average telomere length is currently usually measured in leukocytes obtained from a blood sample. When considering the statistics of a sizable population, average telomere length tends to trend downwards over a lifetime. Telomeres form a part of the complex mechanism that limits somatic cell replication: they shorten with each cell division, and cells with very short telomeres self-destruct or become senescent, ceasing to replicate in either case. Stem cells deliver a supply of new somatic cells with long telomeres to make up the numbers. So average telomere length is a blurred measure of stem cell activity and pace of cellular replication - and in the immune system the latter is highly variable, depending on the current state of health and presence of threats. Telomere length thus varies considerably between individuals of a similar age and health status, and also over quite short periods of time for any given individual. Even in smaller groups, the statistical association with aging can be weak to non-existent. All of this means that telomere length isn't all that helpful as a guide for medical decisions or as a way to evaluate the state of aging.
The associations between mortality and traditional biomarkers such as blood pressure, cholesterol, and body mass index (BMI) weaken with age. The search for a definitive aging biomarker is encumbered by the heterogeneity of cellular aging. Post-mitotic cells are not subjected to the replicative stresses experienced by mitotic cells; therefore, some tissues exhibit greater biological aging than others. The highly variable human lifespan highlights that the mere passage of chronological time is not an effective, isolated measure of aging. Biological aging refers to processes that proceed independently of chronological aging that reduce organismal viability and increase vulnerability. Telomeres are regarded by many as the heir apparent of aging biomarkers, recording both chronological and biological age.
A growing body of evidence also indicates that telomeres are responsive to habitual physical activity (PA). Despite the telomere's popular designation as a mitotic clock, the relationship between telomere length and aging is inconsistent and does not meet the requisite biomarker criteria. Closer examination of the association with PA also reveals inconsistencies and methodological confounders. The clinical and public interest in the PA-telomere association is predicated upon several tacit assumptions: (i) mean telomere length is causally associated with biological aging and age-related pathologies and (ii) PA can lengthen mean telomere length and that in doing so; (iii) PA will reduce biological aging and disease burden.
The proposed associations with aging and exercise are biologically plausible. Telomere length holds tantalizing promise as a biomarker; however, a host of evidential inconsistencies and paradoxes must be addressed. Leukocyte telomere length (LTL) is highly variable at birth, a metric influenced by genetic inheritance and paternal age at conception. It reflects lifelong exposure to oxidative and inflammatory burden yet childhood LTL has more predictive fidelity than LTL in adulthood or old age. Oscillating throughout the lifespan, even inexplicably lengthening despite advancing age, mean LTL differs between genders. Attrition rates also differ between genders and appear dependent upon initial telomere length. Shortening trajectories can be further influenced by variable exposure to a wide range of environmental stimuli. The association between PA is more questionable with 50% of studies failing to find a significant association.
Investigations into plausible mechanisms have returned promising yet inconsistent findings. The prevailing consensus is that exercise-induced reductions in oxidative stress and inflammation likely mediate the effect. The possibility that LTL is a physiological epiphenomenon cannot be excluded. Changes in LTL may simply be coincidental processes that reflect, without directly influencing, the primary mechanism. It is likely that telomere length per se is significant only in so much as it reflects the resultant phenotype via pathways such as senescence-associated inflammation. It has been proposed that evolutionary pressures have fine-tuned telomere length to reduce the risk of short and long telomere pathologies, namely atherosclerosis and cancer. The long-term consequences of manipulating telomere length are not well understood and should therefore be approached with equal measures of enthusiasm and evidence.