The National Geographic's Breakthrough on Aging Research
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The National Geographic has been fairly heavily engaged in promoting Breakthrough, a new popular science and technology show that edges its way around the outskirts of topics such as artificial general intelligence, transhumanism, and, of course, the medical control of aging, which in time will lead to extension of healthy life spans and elimination of age-related disease. Judging from what is out so far, this largely has the air of presenting a very watered-down, safe, unambitious vision of these goals to the public at large, while at the same time painting that as edgy and radical. So both condescending and missing the point at one and the same time. Still, they're sinking a fair amount of time and effort into this judging from the panoply of surrounding articles and the high-tech series website with its 3-D vision sphere effect. Also, albeit buried several layers deep in that set of marginally interactive spheres, you'll find video commentary from some of the folk in our community on the topic of radical life extension through medical science: Aubrey de Grey, Jason Silva, Sonia Arrison, Maria Konovalenko, and so forth.

Apart from that, most of what is on offer is focused on research efforts with marginal goals, such as the metformin trial that aims to be one small step towards very slightly slowing human aging, and researchers who believe that there is little more that can be done than this. For those who reject the SENS view of rejuvenation through targeted damage repair, or similar visions based on the Hallmarks of Aging viewpoint, research plans that could lead to radical life extension within decades if fully funded, there is little to see but a long, very expensive process of cataloging all of cellular metabolism and all of its age-related dysfunctions, and along the way using the traditional process of drug discovery to try to eke out very tiny beneficial alterations to the way in which aging occurs. This is a disappointing vision for anyone to be stuck embracing in a time of radical and rapid progress in biotechnology.

What Do Centenarians Know That the Rest of Us Don't?

Only about 5 people out of 1,000 live longer than a century. For the most part, these people get the same illnesses as everyone else - they just get ill a few decades later. Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, is trying to understand why. He's been studying large numbers of centenarians who share similar genetics. Barzilai is conducting a major study on the diabetes drug metformin, which he has shown can delay the diseases of aging in animals.

"You have to be careful. Is metformin going to be good only? We hope. For 60 years, millions of [people have used it] and nothing bad has happened. But we'll see. Metformin is the way to pave the road. Once the pharmaceuticals jump into this field, we will get better drugs. That's why we think the next decade is really exciting. The fountain of youth is not what we're doing, but this is the first time that we understand enough about the biology and mechanisms [of aging] so we can really think of drugs that can help us."

The Secrets to Unlocking a Longer Life

Aging might not be such a crisis if people not only lived longer, but also stayed healthier and were able to continue to lead productive lives. That's why researchers are working to solve some of the mysteries of aging, and to figure out ways to counteract its effects. And while they haven't yet found a way to slow the aging process, in recent years they've made promising progress.

In recent years, scientists have discovered that longevity apparently has less to do with lifestyle than genes. A study published in 2011 found that those who made it to 95 or older were no more virtuous than the rest of us when it came to what they ate, how much they exercised, and whether they smoked or drank. Indeed, only 43 percent of male centenarians - those over 100 years old - reported engaging in regular exercise of moderate duration. 24 percent of long-lived men consumed alcohol on a daily basis, a slightly higher rate than the general population. "The study suggests that centenarians may possess additional longevity genes that help to buffer them against the harmful effects of an unhealthy lifestyle."

Of interest, there is a small section on senescent cell clearance stuck in the middle of that second article on longevity genes. This is the trouble with translating the essence of longevity science and its goals to the public at large. Those tasked with that effort are usually incapable of determining the difference between lines of research that absolutely cannot ever, even in principle, greatly extend healthy human life and produce rejuvenation, versus those that can. To them there is no difference between (a) hunting for genetic differences that raise the odds of living to be a centenarian from exceedingly low to slightly less exceedingly low, with an eye to giving other people that tiny extra boost to the odds, and (b) work on clearing senescent cells, which is one of the ways of repairing the fundamental causes of aging that could produce significant rejuvenation for any patient. It is all the same to the eyes of the layperson: here is a scientific program, here the scientist is working on something related to aging and longevity, check the box, move on.

I hear occasional complaints that I am partisan in my support of damage repair over, for example, drug discovery or epigenetic alteration as an approach to treating aging. That is because from where I stand the evidence strongly supports SENS-like programs aimed at damage repair as the best, indeed the only, way to achieve radical life extension soon enough to matter. There is a big, big difference in expected outcomes between the likes of carrying out trials for metformin and the likes of trying to make senescent cell clearance a viable treatment. It isn't all the same, and we are still stuck in the situation wherein most of the funding that comes into aging research is going to what is in effect purely investigative science, slightly dressed up with hopes of results because that works to raise funding, but like the metformin trial and the genetic studies in centenarians, these are efforts likely to produce nothing of use beyond more data on metabolism and aging. That's great in the pure science world, where no data goes to waste, but it won't get us to actual, working rejuvenation therapies. There are solid, sensible reasons for being an advocate of SENS and similar efforts, and front and center is the point that, given even a fraction of the funding that went to sirtuin development, SENS is much more likely to produce results that are big enough and happen soon enough to matter to you and I personally.

Nrf2 in Aging and Longevity
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The transcription factor nrf2 regulates levels of antioxidant proteins, a part of the response to everyday cellular stress, such as that induced by raised mitochondrial activity and greater generation of reactive oxygen species (ROS) during exercise. Greater nrf2 activity shows up in long-lived species and in the modest slowing of aging that can be achieved via hormesis in some species. Here is an open access review paper on this topic:

The role of Nrf2 in responding to cytotoxic stressors is well defined. However, only within the last few years have studies elucidated how Nrf2 function changes with age and how changes in Nrf2 activity contribute to the aging phenotype. Aged mice show similar losses in cellular redox capacity to those observed in Nrf2 knockout mice, suggesting that Nrf2 dysregulation with age may be responsible for the loss of cellular redox status. Diminished Nrf2 target gene expression with age is accompanied by increased muscle ROS production, glutathione depletion, and increased oxidant damage to proteins, DNA, and lipids in both humans and rodents. Therefore, given that Nrf2 activity decreases with age alongside increased oxidant stress, interventions that activate Nrf2 may impact the aging process and longevity.

Support for the role of Nrf2 in regulation of lifespan comes from Nrf2 gain of function and loss of function studies. For example, experimental deletion of the antielectrophilic gene glutathione transferase (gGsta4) activated Nrf2 and significantly extended lifespan in mice. This mutation increased electrophilic lipid peroxidation products and increased nuclear Nrf2 activity by 43% and 38% in liver and skeletal muscle, respectively. The authors propose that deletion of this glutathione transferase gene resulted in chronic moderate Nrf2 activation and presumably elevated downstream Nrf2 signaling throughout the mouse lifespan. Studies of the Nrf2 homolog SKN-1 in Caenorhabditis elegans (C. elegans) further suggest that Nrf2 may be implicated in longevity processes. Upon activation, SKN-1 upregulates genes involved in the oxidative stress response, including many orthologs to those regulated by mammalian Nrf2. Similar to mouse Nrf2 knockouts, SKN-1 mutants show diminished resistance to oxidative stress and shortened lifespan. On the other hand, moderate overexpression of a constitutively active SKN-1 increases lifespan, alongside increased resistance to oxidative stress.

The naked mole rat is an exceptionally long-lived species, with a lifespan four times longer than similarly sized rodents, thus making the naked mole rat an important model for longevity studies. Naked mole rats do not have typical lifespan curves in which mortality rates increase with age, but rather they experience few of the biological changes typically associated with aging. Naked mole rats also have significantly elevated proteasome quality control mechanisms. The high breakdown and clearance of damaged proteins is suspected to be largely due to increased Nrf2 expression. In support of the hypothesized role of Nrf2 in naked mole rat longevity, under nonstressed conditions, naked mole rats have greater protein levels of Nrf2 and greater expression of Nrf2-regulated enzymes in fibroblasts and liver. These data suggest Nrf2 may be responsible for the heightened quality control mechanisms in naked mole rats and may be associated with their exceptional longevity.


A Mechanism By Which Amyloid-β Attacks Synapses
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Researchers here provide evidence for a fairly direct link between the growing levels of amyloid-β associated with Alzheimer's disease and the loss of synapses characteristic of the condition. Since the mechanism is so direct, success in present efforts to clear amyloid-β from the brain, such as via immunotherapy, should also minimize this part of the pathology of Alzheimer's disease:

"One of the first signs of Alzheimer's disease is the loss of synapses - the structures that connect neurons in the brain. Synapses are required for all brain functions, and particularly for learning and forming memories. In Alzheimer's disease, this loss of synapses occurs very early on, when people still only have mild cognitive impairment, and long before the nerve cells themselves die. We have identified a new molecular mechanism which directly contributes to this synapse loss - a discovery we hope could eventually lead to earlier diagnosis of the disease and new treatments."

The team studied a protein in the brain called neural cell adhesion molecule 2, or NCAM2 - one of a family of molecules that physically connects the membranes of synapses and help stabilise these long lasting synaptic contacts between neurons. Using post-mortem brain tissue from people with and without the condition, they discovered that synaptic NCAM2 levels in the part of the brain known as the hippocampus were low in those with Alzheimer's disease. They also showed in mice studies and in the laboratory that NCAM2 was broken down by another protein called beta-amyloid, which is the main component of the plaques that build up in the brains of people with the disease. "Our research shows the loss of synapses is linked to the loss of NCAM2 as a result of the toxic effects of beta-amyloid. It opens up a new avenue for research on possible treatments that can prevent the destruction of NCAM2 in the brain."


A Few Recent Research Results on Fitness, Exercise, and Age-Related Decline
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It is no big secret that regular exercise and greater fitness leads to better health and a longer life expectancy, though it remains uncertain as to where the point of greatest benefit lies. What is the dose-response curve for exercise? How does it vary by circumstances and type of exercise? Given the glacial pace of demographic studies, I fully expect good answers to those questions, with robust data behind them, to arrive only decades from now, after the point at which the first rejuvenation therapies exist. What we know today about exercise and aging, gathered from large long-running studies of past decades, is but an outline of the full picture. Athletes at the top of their profession go on to live from a few years to a decade longer on average than the rest of the population, but the data doesn't tell us whether that is because of exercise and fitness, or because only more robust people tend to succeed at becoming professional athletes. At the other end of the scale, there is a few year difference in life expectancy and sizable health difference in the outcomes resulting from being sedentary versus undertaking regular moderate exercise. It is much more certain that this is an effect of the choice to work on fitness versus the case that more resilient people tending to exercise more frequently.

When it comes to a high expectation of positive results for the future of your health, there really are only three options at the present time: regular moderate exercise, some form of calorie restriction or equivalent intermittent fasting, and working to accelerate the right research programs, such as through philanthropic donations. In my eyes that means SENS and SENS-like work focused on the repair of the cell and tissue damage that causes aging, but other people will have other opinions. As for any of the other stuff that the supplement and anti-aging industry will try to sell you on, it is either the case that the scientific evidence is sparse, sketchy, and changeable, the benefits are small and uncertain in comparison to exercise or calorie restriction, or the solid scientific consensus is that there is no benefit.

In an age of rapidly progress in biotechnology, and thus the potential for radical advances in medicine from decade to decade, it makes sense to keep yourself fit. Quite aside from better long-term health being a more pleasant and less expensive experience than worse long-term health, unlike our ancestors we now find ourselves in a situation in which every extra year counts. Will we live to enjoy the first therapies capable of repairing the causes of aging and thus producing at least partial rejuvenation, or will we miss out? That's up to us, not just by staying fit, but more importantly by helping to speed progress towards the development of these therapies. On this topic, here are a couple of recent research publications that, like many others of a similar nature, are an incentive to stay fit and avoid more of the consequences of aging:

Can physical exercise enhance long-term memory?

Exercise can enhance the development of new brain cells in the adult brain, a process called adult neurogenesis. These newborn brain cells play an important role in learning and memory. A new study has determined that mice that spent time running on wheels not only developed twice the normal number of new neurons, but also showed an increased ability to distinguish new objects from familiar objects.

As rodents prefer to spend more time with novel objects than familiar ones, the researchers first exposed the mice to two identical objects (cones or pyramids, in either black or white). After 1.5 hours, one of the objects was replaced with a new object (cone for pyramid or vice versa) and the mice were observed. After 24 hours elapsed, the new object was again swapped, either with a similar object (same color but different shape) or a distinct object (different color and shape). After the short 1.5-hour interval, both running and sedentary mice were able to distinguish similar and distinct objects. However, after 24 hours, a difference was observed. Whereas distinct objects were remembered and recognized by both cohorts of mice, only the running mice could faithfully distinguish similar looking objects. Investigators determined therefore that the running mice had developed better pattern separation capabilities than sedentary mice.

To investigate further, the researchers looked for changes in the brains of the mice. By using markers that could identify newly-formed brain cells, they found that running mice developed about twice as many new cells, and those cells had longer dendrites, compared to the sedentary mice, which facilitates the formation of new synaptic contacts between the nerve cells.

Walking faster or longer linked to significant cardiovascular benefits in older adults

In a large prospective community-based study of older Americans, modest physical activity was associated with a lower risk of cardiovascular disease (CVD). This was true even among men and women older than age 75 at baseline - a rapidly growing population for whom regular activity has been advised, but with little supportive empirical evidence. The researchers studied 4,207 men and women who had been enrolled in the Cardiovascular Health Study (CHS) and who were then followed for 10 years. After adjustment for other risk factors and lifestyle behaviors, those who were more active had significantly lower risk of future heart attacks and stroke. Adults who walked at a pace faster than three miles per hour (mph) had a 50%, 53%, 50% lower risk of coronary heart disease (CHD), stroke and total CVD, respectively, compared to those who walked at a pace of less than two mph. Those who walked an average of seven blocks per day or more had a 36%, 54% and 47% lower risk of CHD, stroke and total CVD, respectively, compared to those who walked up to five blocks per week. Those who engaged in leisure activities such as lawn-mowing, raking, gardening, swimming, biking and hiking, also had a lower risk of CHD, stroke and total CVD, compared to those who did not engage in leisure-time activities.

Higher resting heart rate linked to increased risk of death from all causes

A higher resting heart rate is associated with an increased risk of death from all causes in the general population, even in people without the usual risk factors for heart disease, according to new research. Current evidence for resting heart rate and risk of death and risk of death from heart disease is inconsistent. To understand if resting heart rate is correlated with an increased risk of death, researchers assessed 46 studies involving 1,246,203 patients and 78,349 deaths from all causes, and 848,320 patients and 25,800 deaths from heart disease. "Results from this meta-analysis suggest the risk of all-cause and cardiovascular mortality increased by 9% and 8% for every 10 beats/min increment of resting heart rate. The risk of all-cause mortality increased significantly with increasing resting heart rate in a linear relation, but a significantly increased risk of cardiovascular mortality was observed at 90 beats/min ... consistent with the traditionally defined tachycardia threshold of 90 or 100 beats/min for prevention of cardiovascular disease."

The authors found that people with a resting heart rate of more than 80 beats/min had a 45% higher risk of death from any cause than those with a resting heart rate of 60-80 beats/min, who had a 21% increased risk. However, the absolute risk is still small. Findings were similar for people with cardiovascular risk factors.

Resting heart rate is correlated with fitness, and becoming fitter tends to reduce it. Given the relationship between fitness and mortality, this is probably enough to explain the results observed in the last study noted above.

An Interesting Opinion on Metformin
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The evidence for metformin to slightly slow the aging process is all over the map. It is sketchy and contradictory in comparison to the robust results from rapamycin, for example. This isn't preventing a coalition of researchers from pushing forward on a clinical trial with the FDA, but I suspect that trial is much more a means of changing the FDA position on treatments for aging, which are currently not permitted, than an attempt to show results from metformin. Metformin is useful there because it is an established drug with a much lower set of regulatory barriers for reuse in other contexts, making it harder for regulators to throw roadblocks in the way of a trial to treat aging.

A researcher offers an interesting opinion on metformin in this open access paper. In his view the evidence for modestly reduced cancer rates resulting from metformin use is already good enough that, given the very low cost of the drug, it should be formally adopted and verified for cancer prevention in the general population. This is perhaps best considered in the context of the debate of two years ago over whether rapamycin extends life by reducing cancer risk or slowing aging:

During the last decade, there has been a burst of interest in the antidiabetic biguanide metformin as a candidate drug for cancer chemoprevention. Analysis of the available data has shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters in a wide range of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. It is very important to note that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides.

The history of biguanides in oncology started in the 1970s, is rather dramatic, and seems not to come to "a happy end" at the present time. The first publications in 1974-1982 showing the high potential of PF and BF in prevention of spontaneous and induced carcinogenesis were not met an interest adequate to the degree of real importance of these finding. Whereas both in vitro and in vivo experiments provide new evidence of anti-carcinogenic potential of biguanides, and the majority of clinical observations clearly demonstrates protective effect of MF in relation to many localization of cancer, there are some publications on results of clinical trials that are inconclusive and sometime were demonstrated adverse effect of MF. Recently a researcher explaining possible reasons for this inconsistency cited the rather sardonic comment of a leading scientist in the field: "The problem with metformin is it's cheap, it's widely available, it has a great safety profile, and anyone can use it". Really, it is difficult to say better... In PubMed, under the words such as "metformin and cancer" the number of indexed papers were increasing exponentially from zero in 1990 to more than 2500 last September. Among them around 185 reviews on the topic were published just in the last 5 years. There are too many works and still no final conclusion. It may be the time to make this long story short; we believe that efficacy of MF should be evaluated according to criteria, experience and rules of the WHO International Agency for Research on Cancer.


Yet More Mapping of Age-Related Epigenetic Changes
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Epigenetic changes occur constantly, altering the production of proteins in response to circumstances, and thus changing cell and tissue behavior. Some of these changes occur in reaction to the cell and tissue damage of aging, and are characteristic enough to allow development of a measure of biological age, an assessment of how damaged an individual is. This is a work in progress, but a good, cheap measure of biological age is a needed tool in the field of longevity science. Currently the only way to establish that potential rejuvenation treatment works in the sense of extending healthy life is to wait and see what it does to life expectancy, which makes exploration of ideas prohibitively expensive, and slows progress across the whole field:

To examine the changes that occur in blood as an individual ages, researchers conducted an extensive study using thousands of patient blood samples. In a remarkable show of replication, the study was initially performed with blood samples from individuals of European ancestry and then replicated in additional European ancestry samples, totaling an amazing 14,983 individual European ancestry samples. The study was then extended to various ethnic groups, including samples from individuals of Hispanic, African, or Native American ancestry. The study identified 1,497 genes in blood cells and/or brain tissue that showed significantly differential expression patterns in older individuals when compared to younger individuals.

There were three distinct groups of genes that were negatively correlated with chronological age. The first group included three subgroups: ribosomal genes (factories on which a RNA is translated into a protein), mitochondrial genes (energy factories of the cells), and genes associated with DNA replication and repair (DNA maintenance and fidelity). All of the genes associated with these subgroups are vitally important to the health of a cell and tissue. The second large group consisted of genes associated with immunity. The third large group was composed of genes that code for the actual ribosomal subunits. Decreased gene expression could help explain the decreased "health" of older cells and increased mutation rates in older cells. There were also four groups of genes positively correlated with age, which were focused on cellular structure, immunity, fatty acid metabolism, and lysosome activity.

Another interesting finding in this study involved epigenetic patterns, specifically methylation on cytosines (one of the four nucleotide bases in DNA). This study showed that those genes whose expression pattern changed with age were highly enriched for the presence of regulatory cytosines. This could indicate how gene expression is controlled as the individual ages. There are several targeted methylation therapies in development that might potentially offer the ability to effectively and safely alter these methylation patterns for therapeutic purposes. The authors found that by combining the transcriptomic expression patterns and the epigenetic patterns a "chronological" age predictor could be used to better understand an individual's "age" in terms of health. Further refinement is needed, but this type of predictor could have a substantial impact on prediction, diagnosis and treatment of individuals, perhaps even allowing for preventive treatments before symptoms progress to disease level changes.


The MitoAge Database: Mitochondrial DNA and Longevity Compared Between Numerous Species
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Here I'll point out a recent addition to the set of open data interfaces that are both interesting and relevant to aging research: the MitoAge database, cataloging mitochondrial DNA and longevity in a wide range of species. Mitochondria, the descendants of ancient symbiotic bacteria, swarm in herds inside our cells. The research of past years provides compelling data to suggest that the details of mitochondrial composition, particularly in respect to their resistance to oxidative damage, has a fair-sized effect on life span. Why is oxidative damage an important consideration? Because mitochondria work to create energy store molecules used to power the rest of the cell, a process that involves the generation of reactive oxidizing molecules as a side-effect. A cell is a fluid sack of structures and chemical reactions, all of these components moving around in close proximity, engaged in constant activity. Newly created oxidants don't have far to go in order to react with some important piece of molecular machinery in a way that causes damage and dysfunction. Some are rendered harmless by natural antioxidants, but damage is constant and ongoing, albeit usually repaired very rapidly.

The closest structure for mitochondrially generated oxidants to react with and harm is the mitochondrion itself, and in particular its DNA. Every mitochondrion has at least one copy of the left-over remnant genome from its bacterial ancestry, encoding necessary proteins used in its structure and energy store construction machinery. This DNA isn't as well protected and repaired as is nuclear DNA, and certain rare forms of damage can produce mitochondria that are both dysfunctional and more likely to replicate and survive within their cell. It isn't completely open and shut that this is the way in which cells become overtaken by broken mitochondria and go on to harm surrounding cells and tissues; this contribution to the aging process might have more to do with errors in mitochondrial replication than oxidative damage, for example. But there is certainly a good solid correlation in mammals between longevity and mitochondrial resistance to oxidative damage. When we look at birds and bats, the details of their mitochondrial biochemistry is entwined with the metabolic requirements of flight, and the comparatively long life spans in these species when considering their size may once again be a factor of adaptation to higher levels of oxidative stress generated during flight. Further, there are the studies showing modestly increased health or life span in mice due to increased levels of natural mitochondrial antioxidants, or mitochondrially targeted antioxidant drugs.

To my eyes all of this work and knowledge as a whole should really be taken as a big pointer to suggest that repair of damaged mitochondria is an important part of any future regenerative medicine to produce rejuvenation. The SENS Research Foundation has helped to pioneer the allotopic expression approach to maintaining undamaged mitochondria that is currently under clinical development for inherited mitochondrial disease at Gensight, and continues to work towards a more comprehensive version of the treatment that can be used to treat aging. Funding - as ever - is very limited for this line of research given the potential benefits, but the fastest path to results remains to get this working in mice and see what happens. Given what we know of the effects of more subtle and limited manipulations in mitochondrial biochemistry, we should probably expect the benefits to health and longevity to be sizable enough to draw attention.

Welcome to MitoAge!

The rapidly increasing number of species with fully sequenced mitochondrial DNA (mtDNA), together with accumulated data on longevity records, provide new fascinating opportunities for the analysis of the links between mtDNA features and longevity across animals. To facilitate such an analysis, and to support the scientific community in carrying it out, we developed MitoAge - a curated, publicly available database, containing an extensive collection of calculated mtDNA data records, and integrated it with longevity records. The MitoAge website also provides the basic tools for comparative analysis of mtDNA, with a special focus on animal longevity.

Mitochondria are the most "hard-working" organelles and the only organelles in the animal cell that have their own genome. They have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases1. We and others have shown strong correlative links between mammalian maximum lifespan and mtDNA base composition. In particular, the mtDNA GC content appears to be an independent and powerful predictor of mammalian longevity.

MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity

The stability of the mitochondrial DNA (mtDNA) is vital for mitochondrial proper functioning; therefore, changes in mtDNA may have far-reaching consequences for the cell fate and, ultimately, for the whole organism. Not surprisingly, due to a key role in energy production, generation of damaging factors (ROS, heat), and regulation of apoptosis, mitochondria and mtDNA in particular have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases.

We developed the MitoAge database containing calculated mtDNA compositional features of the entire mitochondrial genome, mtDNA coding (tRNA, rRNA, protein-coding genes) and non-coding (D-loop) regions, and codon usage/amino acids frequency for each protein-coding gene. MitoAge includes 922 species with fully sequenced mtDNA and maximum lifespan records. The database is available through the MitoAge website, which provides the necessary tools for searching, browsing, comparing and downloading the data sets of interest for selected taxonomic groups across the Kingdom Animalia. The MitoAge website assists in statistical analysis of different features of the mtDNA and their correlative links to longevity.

Slowing Aging Slows Parkinson's Development, Even When Caused By Genetic Mutations
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In some patients Parkinson's disease is associated with genetic variants, most likely because those differences increase susceptibility to damage in the small but critical population of neurons that are destroyed as the disease progresses. It is all very much a matter of levels of damage, however, and so we shouldn't be surprised to see that established methods of modestly slowing aging in laboratory animals also slow the progression of Parkinson's-like model conditions created through genetic alteration. Aging, after all, is also a matter of accumulating damage - the less damage you have, the less aged, dysfunctional, and frail you are.

Scientists have shown in disease models that slowing aging reduces degeneration related to Parkinson's. "It is unknown why symptoms take many decades to develop when inherited mutations that cause the disease are present from birth. Aging is the greatest risk factor for developing Parkinson's - we believe changes that occur during the aging process make brain cells more susceptible to disease-causing mutations that don't cause issues in younger people."

In the brain, Parkinson's is marked by the dysfunction and death of the nerve cells that produce dopamine - a chemical that plays a key role in many important functions, including motor control. Clumps of a protein called alpha-synuclein also are found in brain cells of most people with Parkinson's, although scientists are still trying to pin down their exact role. As part of their search for ways to prevent the disease, researchers delayed the aging process in genetic models of Parkinson's disease. They demonstrated that slower aging imparts protection against the loss of dopamine-producing cells in the brain and decreases the formation of alpha-synuclein clumps - ­both hallmark features of Parkinson's. "This work suggests that slowing aging can have protective effects on the brain cells that otherwise may become damaged in Parkinson's. Our goal is to translate this knowledge into therapies that slow, stop or reverse disease progression."

The team used the worm Caenorhabditis elegans as a genetic model for Parkinson's. Thanks to its simple and well-mapped nervous system, and the ease of genetic manipulation and maintenance of the worm, C. elegans is well-suited for the identification of novel treatment strategies for neurodegenerative diseases. Worm models of Parkinson's disease that expressed either a mutated LRRK2 gene or a mutated alpha-synuclein gene - both of which cause Parkinson's - were crossed with a long-lived strain of the worm to create two new strains with longer lifespans. The researchers found that long-lived LRRK2 and alpha-synuclein worms lost dopamine neurons at a much slower rate than their counterparts with normal lifespans. In fact, the long-lived LRRK2 worms had more dopamine neurons left on day 30 of the study than the LRRK2 worms with a normal lifespan of three weeks had on day eight of adulthood. Slowing aging also effectively reduced motor deficits related to the loss of dopamine-producing cells and eliminated the increased sensitivity to stress shown by worms with a normal lifespan.


The Question of Whether to Build Rejuvenation Therapies
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Should we build rejuvenation therapies? Hell yes. Are we? Barely, as nowhere near enough of an effort is being made. This is an opinion piece by Aubrey de Grey of the SENS Research Foundation:

Aging is a hot topic among the chattering classes these days. What with biotech companies like Calico and Human Longevity Inc. being founded with the mission to defeat aging, and venerable institutions such as Prudential proclaiming the imminence of superlongevity on billboards, there's no denying that this is a time of great interest in our oldest and deepest-held dream - to escape from the tyranny of inexorable and ultimately fatal physiological decline.

But hang on - is the buzz around aging really reflective of what's being done to realize this goal? The briefest dispassionate analysis reveals a different story altogether. The proportion of government spending allocated in the industrialized world to diseases and disabilities of old age is appropriately high, but it is overwhelmingly dedicated to the transparently quixotic approach of attacking those ailments directly - as if they were infections - rather than attacking their lifelong accumulating causes. The latter approach is the focus of biomedical gerontology. Researchers in this field recognize that any direct attack on late-life disease is doomed to become progressively less effective as the causes of those diseases continue to accumulate, so they focus instead on those causes - the "damage" that the body inflicts on itself throughout life in the course of its everyday operation. But they comprise a tiny coterie of scientists - far too few, and with access to far too little funding, to allow progress to occur at anywhere near the maximum rate that the simple technical difficulty of the problem would allow.

I believe that the main reason for this tragic myopia is a phobia about aging so ancient and deep-seated that it overpowers the rationality of nearly all of us, even the most intelligent and educated. Aging holds us in a psychological stranglehold, preventing us from even contemplating the idea of its medical conquest. Thus it is that grown adults find it possible to argue that we should forever continue to let everyone endure the number one cause of human suffering. Unfortunately for us - by which I mean, for the whole of humanity - those adults include the overwhelming majority of the people who control enough money (whether their own, their company's or the taxpayer's) to make a difference. Even without getting into the debate about what approaches to this challenge are the most promising, one can no longer escape the fact that most biomedical gerontologists now agree that we are approaching a time of sharply accelerated progress in extending healthy lifespan. Except, of course, by letting that expert opinion go in one ear and out the other. And that, I'm afraid to say, is what most decision-makers are still doing. The marginalization of anti-aging research is our most shameful humanitarian failure.


The Methuselah 300 Monument is Unveiled
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The Methuselah Foundation has unveiled the Methuselah 300 monument in the US Virgin Islands, a lasting record of the generous donors of the Methuselah 300 who have helped fund the work of the Methuselah Foundation over the past decade: the M Prize for longevity science; the seed funding of bioprinting company Organovo; the SENS rejuvenation research programs and creation of the SENS Research Foundation; the launch of the New Organ prize series; and much more.

The Methuselah Foundation was the first longevity science initiative that I chose to materially support with my donations and my time. The third post I wrote here at Fight Aging! back in 2004 covers the just-getting-started initiative of the Methuselah 300: aiming to find a group of regular donors to contribute to bold initiatives in aging research. It was an ambitious plan at a time when raising funding to accelerate progress towards rejuvenation therapies was near unheard of, mocked by the press and the scientific establishment where it did happen, and all in all considerably harder than it is today. But why is it now easier to raise funds for rejuvenation research, and why is it now the case that up and coming scientists can talk seriously about treating aging without risking reputation and career? In large part because the Methuselah 300 worked, people joined in to a degree not seen in earlier initiatives with similar aims, the Methuselah Foundation became a going and influential concern within the small aging research community atop the foundation provided by 300 member donations, and the staff and allies of the Methuselah Foundation went on to change the culture of that community, spinning off the SENS Research Foundation along the way, having a hand behind the scenes in many important activities and decisions.

This is something like the eleven thousandth post at Fight Aging!, and a decade has passed since the first member of the Methuselah 300 sent in the first donation to help fund the then small M Prize for longevity science. The reasons for joining the 300 are just the same as they were back then, with the additional guarantee that now it isn't a step into the unknown. You might read Michael Rae's call to action from that time, for example. Joining the Methuselah 300 is a way to make a real difference to the future of health and aging, to materially support an organization with a proven track record of getting things done in longevity science. Just this year, for example, the Methuselah Foundation joined with the SENS Research Foundation in providing seed funding to Oisin Biotech, a startup company aiming to build a viable senescent cell clearance therapy, a technology we hope to see reach the clinic in the near future, the first true rejuvenation therapy capable of removing some of the damage that causes aging and age-related disease.

The Methuselah 300 Monument

In 2005, The Methuselah 300 initiative began with a few brave and dedicated people willing to fight for life itself. These individuals are now honored by a monument in St. Thomas. Their story is presented by the founders of the Methuselah Foundation in the following video. In it, we pay tribute to their continued courage and generosity, which fuels the real hope for extended healthy human life.

Will you join the legacy?

Methuselah Foundation Announces the Official Unveiling of the Methuselah 300 Monument

In 2003, the Methuselah Foundation was formed to take action on a remarkable idea: that the world's greatest scientific and medical minds, given the right spark of innovation, could bring about sweeping changes in the longevity and quality of life for people everywhere. Exciting and innovative ideas find like minds, and the Methuselah Foundation moved quickly to encourage innovative creativity in the fields of medical and longevity research. With the establishment of the first "M Prize", scientific researchers saw this prize as an opportunity to be rewarded for results rather than just research itself, and teams of scientists and doctors began to get on board.

None of this was accomplished alone. Integral to the Methuselah Foundation and it's work are the men and women who early on saw the amazing possibilities the foundation's work could accomplish. These men and women were the foundation of a collective group that came to be known as the 300. Since 2005, 150 dedicated men and women have committed to giving $25,000 over 25 years to help us eradicate needless suffering and extend healthy human life. In the over 10 years since the foundation was formed with the help of these ones, research has reached the point that things once considered impossible are now on the horizon; advances like bio-printing organic material, and the organic generation of new organs.

In the foundation's desire to thank the selfless compassion and generosity of this group who continues to make these things possible, we are pleased to announce the official unveiling of the Methuselah 300 Monument! Just as the original 300 Spartans were later memorialized in a monument at Thermopylae, we have memorialized our own 300 with a unique monument located on a breathtaking hillside in St. Thomas in the U.S. Virgin Islands. The monument total size including surround is 9 feet wide x 17 feet long, and the granite plaques are 4 feet wide by 10 feet long. This monument will draw attention to those who generously give so that other's lives may be extended, or have their quality of life raised by the research the Methuselah foundation continues to inspire and encourage. The monument will be available for all to see by webcam at anytime; seeing not only the names already inscribed, but also the names of future 300 members to be added.

We would also like to extend the invitation for you to become a member of the 300, or support the foundation's work to whatever extent you are able. We will continue working to accomplish our goal of "making 90 the new 50 by 2030"! Will you join us?

Energy-Carrying Molecules to Boost Aging Mitochondria?
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Here I'll point out the latest in the Question of the Month series from the SENS Research Foundation, in which the staff are far more polite than I regarding the unmerited hype that seems to accompany both supplement research in general and research emerging from the Sinclair lab at Harvard in specific:

Q: In recent months, I've seen quite a lot of promotional material for a dietary supplement called nicotinamide riboside (NR). The companies involved say that Harvard researchers showed that this supplement restores mitochondrial function in the cells of aging mice, completely reversing the aging process in muscles. Some of them add that other research has shown that it improves metabolism, fights fat and obesity, and is protective of brain function. What do you think of this supplement?

A: It must be clarified that the substance used in the Harvard research was not actually NR, but another compound called nicotinamide mononucleotide (NMN). But NMN is unsuitable for oral supplementation, so the Harvard researchers injected their mice with NMN rather than giving it to them in their feed. With the excited coverage that greeted the research, supplement companies have promoted NR as a substitute, because it was already in production and can be taken orally. Because NR is a precursor to NMN, which in turn is used for the synthesis of the energy shuttle molecule nicotinamide adenine dinucleotide (NAD), many supplement vendors assert or imply that the results with NMN can also be gained with NR.

That all may sound promising, and it certainly makes for effective marketing copy. But no study has actually been done demonstrating that NR has similar effects to NMN in the muscles of otherwise-healthy aging mice. In fact, one study found that high-dose NR supplementation was unable to increase NAD+­ levels in muscle tissue or the mitochondrial fraction of normal, healthy mice. Additionally, overexpressing the gene that converts NR to NMN in these animals' muscles still didn't affect muscle mitochondrial function in the way that the Harvard researchers reported with NMN, suggesting that the effects observed with injected NMN may involve some kind of systemic response to having NMN itself circulating in the bloodstream. This casts considerable doubt on the assumption that either NR, or some other supplement that raises cellular NAD+­ levels, will replicate the effects of NMN on aging muscle. Additionally, interpretation of the Harvard report is greatly hampered by the lack of information of the animals' weight or food intake, which raises the possibility of effects mediated by calorie restriction or (contrariwise) by the simple overfeeding of all the animals in the study.

It's also important for readers of the press coverage to understand just what was involved when such stories reported that NMN treatment "reversed the effects of aging" on the mice's muscles. Readers would be forgiven for imagining the muscles of frail, elderly mice suddenly swelling to youthful size, able to perform tiny rodent bench presses with the strength and endurance of much younger animals. In reality, though, as the investigators were careful to point out in the original scientific paper, while their treated animals' muscle cells exhibited biochemical evidence of improved ("rejuvenated") metabolism and insulin-stimulated glucose uptake, "we did not observe an improvement in muscle strength." This important detail was missing from almost all of the reporting in the popular press. While it's possible, as the scientists speculate, that longer-term treatment would have led to some recovery of muscle function, the lack of any observed improvement in actual muscle strength calls into question the functional significance of the biochemical "rejuvenation" they report.


Considering the Possibility of a Type 4 Age-Related Diabetes
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Type 1 diabetes is an autoimmune disease, type 2 diabetes is a lifestyle disease largely caused by being overweight, some researchers have suggested that Alzheimer's disease is a type 3 diabetes, and here evidence is presented for the existence of a type 4 age-related diabetes:

Diabetes is often the result of obesity and poor diet choices, but for some older adults the disease might simply be a consequence of aging. New research has discovered that diabetes - or insulin resistance - in aged, lean mice has a different cellular cause than the diabetes that results from weight gain (type 2). And the findings point toward a possible cure for what the scientists are now calling a new kind of diabetes (type 4). "A lot of diabetes in the elderly goes undiagnosed because they don't have the classical risk factors for type 2 diabetes, such as obesity. We hope our discovery not only leads to therapeutics, but to an increased recognition of type 4 diabetes as a distinct disease."

Researchers set out to compare the immune systems of healthy mice, those with obesity-related diabetes and those with age-related diabetes. The mice with age-related disease, they found, had abnormally high levels of immune cells called T regulatory cells (Tregs) inside their fat tissue. Mice with obesity-related diabetes, on the other hand, had normal levels of Tregs within the tissue, despite having more fat tissue. Normally, Tregs help calm inflammation. Because fat tissue is constantly broken down and built back up as it stores and releases energy, it requires low levels of inflammation to constantly remodel itself. But as someone ages, the new research suggests, Tregs gradually accumulate within fat. And if the cells reach a tipping point where they completely block inflammation in fat tissue, they can cause fat deposits to build up inside unseen areas of the body, including the liver, leading to insulin resistance. "It was a little bit surprising since normally Tregs are supposed to be beneficial for the body."

When the scientists blocked Treg cells from accumulating in the fat by targeting a molecule that the immune cells require, mice no longer developed type 4 diabetes in old age. However, if mice became obese, blocking the Tregs in fat did not prevent type 2 insulin resistance. "It turns out that for this type of diabetes, the treatment is not losing weight. The treatment is actually losing these cells, and we show that it's possible to do that." The researchers now want to find out exactly how Tregs interact with fat tissue and whether the immune cells accumulate in other organs during normal aging. They're also planning studies to see whether the results hold true in humans. "We're working with clinicians to get samples from older, lean people with diabetes to see if this cell type is also implicated in human disease."


Triple Matching of SENS Donations on Giving Tuesday, Coming Up on December 1st
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Giving Tuesday is the Black Friday of the non-profit world, a collaborative event organized across the whole of the non-profit community in which activists and advocates raise awareness, coordinate activities, and inform the decisions that people make about charitable donations at the end of the year. This year Giving Tuesday falls on December 1st. As I'm sure you're all aware, we're in the midst of raising funds for SENS rejuvenation research, the best and most effective of initiatives aimed at bringing aging under medical control. We have a little under $60,000 to go before the end of the year to hit our targets, and I'm pleased to note that if you donate to the SENS Research Foundation on December 1st your donation will be matched threefold - by the Fight Aging! matching fund, the Croeni Foundation, and Aubrey de Grey:

SENS Research Foundation is getting ready to celebrate #GivingTuesday on December 1st. GivingTuesday is now a global event celebrated by supporters of various charities giving to their favorite causes. If you've been planning on contributing to the fight against age-related disease this year, GivingTuesday is a great opportunity to make a difference.

So far, SENS Research Foundation has 3 matching grants set up for GivingTuesday. The first is our FightAging! Challenge which will match every dollar you give us up to $125,000. On GivingTuesday, the first $5,000 we raise will not be doubled or even tripled - it will be quadrupled thanks to the generosity of the Croeni Foundation and Aubrey de Grey. Help us turn $5000 into $20,000 and accelerate the fight against age-related diseases! Donate at on December 1st.

Seize this chance to make a real difference in the future of human health and longevity! The staff and allies of the SENS Research Foundation have demonstrated over the past decade that they can produce real, meaningful results with our donations, pushing forward the state of the art closer to the realization of effective therapies for aging. The potential to fundamentally change the world of medicine is very real: those of us yet to be old have a shot at ensuring that treatments arrive soon enough to prevent us from suffering age-related pain, disability, and frailty. The causes of aging, well-cataloged forms of cell and tissue damage, can in principle be repaired, and the path to doing so is just about as clear as research and development can ever be.

This is the time for it. We stand in the initial years of a revolution in the capabilities and cost of biotechnology. Early stage research in the life sciences has become very cheap; a few tens of thousands of dollars can go a long way in an established laboratory, producing real progress at the cutting edge when spent wisely. Yet much of the necessary, revolutionary work in aging research is only funded by philanthropy, as traditional funding institutions are risk-averse and don't become involved until the prototypes are built, the case proven. In essence all important progress in medicine depends on the early participation of people like you and I, who are both aware of the possibilities, and interested enough in the outcome of greater healthy longevity to help make it happen.

For most people, medical research is invisible. They'll never read about it, never think about it, until it is too late to have made a difference that mattered. Reading this, you have a chance to avoid that scenario. The more that is done now to start the avalanche of rejuvenation biotechnology development, the greater the results decades from now, at a time when aging is encroaching upon your health. Don't let this opportunity slip away: help fund the work of the SENS Research Foundation on the scientific basis needed to bring an end to degenerative aging.

Skepticism of a Causative Role for Telomeres in Aging
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A researcher here takes a skeptical look at telomerase studies, such as those shown to extend life in mice, most likely by boosting stem cell activity. There is a school of thought that suggests the role of telomerase in lengthening telomeres is an important mechanism in the induced longevity attained in these studies, but I think it is correct to be skeptical on this count. Erosion of average telomere length occurs over a life span, but this really does not look like a root cause of degenerative aging. Instead the average length of telomeres in immune cells, where it is commonly measured, appears to be a consequence of some combination of stem cell activity and immune health. In any given tissue, cells with long telomeres are created at some pace by stem cells, telomeres shorten with each cell division, and old cells with short telomeres destroy themselves or become senescent. Stem cell activity declines with age, and it isn't a leap to suggest that this will tend to produce shorter average telomere lengths as the supply of new cells diminishes.

Telomeres are repetitive DNA sequences at the ends of linear chromosomes and serve to maintain chromosome integrity. Additional properties have made telomeres a focus in the biology of aging: (i) telomeres shorten at each cell division due to incomplete replication of their ends; (ii) they are shortened by oxidative damage; and (iii) when telomeres reach a critical length, cells enter a senescent state and cell division ceases. This latter property has been demonstrated in now classic experiments, showing that telomere length predicts the in vitro replicative capacity of human fibroblasts and that over-expressing telomerase - the enzyme that can reverse transcribe telomeric sequence - immortalizes fibroblast cell cultures. These experiments suggest the possible causal involvement of telomeres in the aging process and this hypothesis has increased in popularity since the finding that telomere length predicts human mortality and that, in vivo, human telomeres shorten during aging.

It is rarely acknowledged in telomere biology that such associations do not necessarily dictate causality. Of course in principle associations can never show causality, and experimental evidence is a starting point. Such inference is useful interpreting data in terms of biological mechanism and for policy, but can also be harmful when such causality is prematurely inferred or assumed. This can lead to reduced or misfocused research effort to uncover the mechanisms actually responsible for the associations that are reported or false inference of the associated biology. In the biology of aging it is tempting to infer causality from biomarkers of aging because aging mechanisms remain so elusive. It is therefore not surprising that causality of telomere length in aging is often inferred from associations or from the available experimental evidence.

Here I question such causal involvement of telomeres in aging. I review the telomerase knockout and overexpression studies that are often cited and hailed as providing the necessary evidence for the causal involvement of telomere biology in aging. I collated studies on the effects on longevity and conclude that, together; the results are surprisingly mixed and provide weak support. In the cases where lifespan changed as predicted in response to the manipulation of telomerase, the effect on telomere length was either outside the normal range of telomere shortening or telomere elongation was not conclusively demonstrated, thereby limiting any strong conclusions. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress.


A View of the Important Divide in Longevity Science from the Other Side of the Fence
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Here I'll point out a view of the great divide in aging research from the other side. I have long argued that the most important divide in the field of aging research is between (a) the minority position of those who see aging as an evolved program, so that, for example, epigenetic changes occur that cause altered cellular behavior that in turn leads to an accumulation of damage, dysfunction, and death, and (b) the majority position of those who see aging as a matter of accumulated damage occurring as a side-effect of the normal operation of metabolism, and that damage results in epigenetic changes, dysfunction, and death. There is a horse and a cart, and some argument over which is which.

Researchers in fact know a great deal about the differences between old tissue and young tissue. They have a very good catalog of those differences. They also have a pretty good catalog of the dysfunctions in specific organs and tissues that accompany age-related disease. The middle ground between those two things, the enormously complex biochemical interactions spanning decades of time that produce aging, is much more of a blank spot on the map. Only tiny slices have been mapped, and it is this gap that allows the freedom to theorize over whether change produces damage or damage produces change.

Why is this important? Because whether you stand on one side or the other of this theoretical divide determines which approach to treating aging you should favor. Treatments for aging must aim at root causes to be effective. If change, such as epigenetic change leading to altered levels of proteins in cells, is the root cause of the damage of aging, then treatments should consist of restoring the right protein levels and epigenetic markers rather than addressing damage. But if damage is the root cause of aging then treatments should be repairing that damage. The potential rejuvenation therapies that are on the wrong side of the line will likely be ineffective in comparison to those on the right side of the line.

Obviously, given my support for the SENS approach to treating aging, I'm in the damage camp. I think that the evidence, such as the presence in old tissues of harmful cross-links that our biochemistry cannot break down, strongly supports the view that aging is caused by damage accumulation, and the observed epigenetic and protein level changes are reactions to that damage. Here, however, is a view from the other side, the programmed aging camp:

Aging is an accumulation of damage. If we want to return the body to a more youthful state, we're going to have to repair that damage. Or ... the body never forgets how to be young. Given the appropriate signaling environment, the body will restore itself to a youthful state. The future of medicine is the future of anti-aging medicine. I don't think anyone seriously disputes this. Infectious diseases are a minuscule problem compared to a century ago, and with hygiene, good public health practices, and responsible restraint in applying antibiotics, we may hope to avoid a return to the days when tuberculosis and syphilis were pandemic. We are fast learning to treat congenital disorders, and safe gene therapies are already being tested.

This leaves diseases of old age as the next frontier. To slow the progress of aging, there is no doubt that signaling approaches work in animals, and will work (probably with less efficacy) in humans. Caloric restriction (CR), exercise and other forms of hormesis are the best approaches we know at present. Pills (e.g. metformin) may offer some of the benefits of CR without the hunger, and an "exercise pill" has been proposed. The next step is to actually reverse aging, to restore the body to a more youthful state. Among those of us who advocate research in the technology of age reversal, there are two prevailing paradigms. I am with the school that says the same signaling approach can be extended to trick the body into thinking it is younger than it is, and the body will renew its cells and replace damaged biomolecules on cue. The other school says that once the toothpaste is out of the tube, it's not going back in. We will have to engineer prosthetics, use bioengineering and regenerative medicine to replace body parts that have worn out.

In the beginning, anti-aging medicine was thought to be fanciful, if not impossible. How could human engineering improve on processes that Nature has been perfecting for a billion years? Then a science of regenerative medicine began very slowly chipping away at that conventional wisdom, and a glimmer of hope pointed to promise of fixing the body directly with engineering, at least in the long run. But a funny thing happened along the way. There are indications in many areas that the body knows perfectly well how to rejuvenate itself, and we need only learn to speak the body's (biochemical) language in order to say, "Have at it!" A few people like me are pointing out that this contradicts everything we thought we knew about evolutionary biology, and that the "selfish gene" is in need of an overhaul. But bench scientists are choosing to sidestep this theoretical debate and simply to do the practical thing. They are pursuing a signaling approach because it works.

I would argue that the signaling approach is largely characterized by failure to obtain meaningful outcomes, and at great cost. Just look at the end result of sirtuin research; enough money expended to fully implement SENS rejuvenation programs in mice, and nothing to show for it but greater knowledge of a small slice of our biochemistry. Where there are successes in more recent years, these seem to result from activation of stem cells in old tissues - and restoring stem cell populations is on the SENS agenda - without any accompanying repair of other root cause damage. This will produce benefits, and fortunately it seems that putting damaged cells in damaged tissues back to work has far less of an effect on cancer risk than was feared, but this doesn't do anything to clear out issues such as amyloids, lipofuscin, and persistent cross-links.