Large Genome-Wide Study Finds Only a Few Genetic Influences on Human Longevity

The influence of genetic variants on natural variations in human longevity is a very complex matter. The evidence to date supports a model in which thousands of genes have individually tiny, conditional effects. Near all associations identified in any given study population have failed to appear in any of the other study populations, and effect sizes for the very few longevity-associated genes that do appear in multiple studies are not large in the grand scheme of things. These variants provide a small increase in the odds of living to be very old, but the individuals bearing them are still diminished and damaged by aging. The genetics that determine how cellular metabolism gives rise to variations in aging are of great scientific interest, but there is nothing here that can act as the foundation for therapies that will help people to live significantly longer.

The extent of the role of genetic variation in human lifespan has been widely debated, with estimates of broad sense heritability ranging from around 25% based on twin studies to around 16.1% based on large-scale population data. One very recent study suggests it is much lower still (less than 7%), pointing to assortative mating as the source of resemblance amongst kin. Despite this modest heritability, extensive research has gone into genome-wide association studies (GWAS) finding genetic variants influencing human survival. Only two robustly replicated, genome-wide significant associations (near APOE and FOXO3) have been made to date, however.

An alternative approach is to study lifespan as a quantitative trait in the general population and use survival models to allow long-lived survivors to inform analysis. However, given the incidence of mortality in middle-aged subjects is low, studies have shifted to the use of parental lifespans with subject genotypes, circumventing the long wait associated with studying age at death in a prospective study. In addition, the recent increase in genotyped population cohorts around the world, and in particular the creation of UK Biobank, has raised GWAS sample sizes to hundreds of thousands of individuals, providing the statistical power necessary to detect genetic effects on mortality. A third approach is to gather previously published GWAS on risk factors thought to possibly affect lifespan, such as smoking behaviour and cardiovascular disease (CVD), and estimate their actual independent, causal effects on mortality.

Here, we blend these three approaches to studying lifespan and perform the largest GWAS on human lifespan to date. First, we leverage data from UK Biobank and 26 independent European-heritage population cohorts to carry out a GWAS of parental survival. We then supplement this with data from 58 GWAS on mortality risk factors. Finally, we use publicly available case-control longevity GWAS statistics to compare the genetics of lifespan and longevity and provide collective replication of our lifespan GWAS results.

We identified 11 novel genome-wide significant associations with lifespan and replicated six previously discovered loci. We also replicated long-standing longevity SNPs near APOE, FOXO3, and 5q33.3/EBF1 - albeit with smaller effect sizes in the latter two cases - but found evidence of no association (at effect sizes originally published) with lifespan for more recently published longevity SNPs near IL6, ANKRD20A9P, USP42, and TMTC2. Despite studying over 1 million lives, our standard GWAS only identified 12 variants influencing lifespan at genome-wide significance. This contrasts with height (another highly polygenic trait) where a study of around 250,000 individuals found 423 loci.

This difference can partly be explained by the much lower heritability of lifespan (0.12 versus 0.8 for height), consistent with evolution having a stronger influence on the total heritability of traits more closely related to fitness and limiting effect sizes. In addition, the use of indirect genotypes reduces the effective sample size to 1/4 for the parent-offspring design. When considering these limitations, we calculate our study was equal in power to a height study of only around 23,224 individuals, were lifespan to have a similar genetic architecture to height. Under this assumption, we would require a sample size of around 10 million parents (or equivalently 445,000 nonagenarian cases, with even more controls) to detect a similar number of loci.

Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance in lifespan. We hoped to narrow down the search and discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease.

Link: https://doi.org/10.7554/eLife.39856

Blood-Brain Barrier Dysfunction as an Early Driver of Dementia

The blood-brain barrier surrounds blood vessels in the brain, enforcing restrictions on the passage of molecules and cells between brain and blood supply. Like all bodily systems, the blood-brain barrier breaks down with aging, yet another consequence of rising levels of cellular damage and disarray. The passage of inappropriate cells and molecules into the brain is thought to cause a range of issues, but, as is the case for all aspects of the biochemistry of the brain, this is a very complex environment and set of processes. Firm answers are ever elusive, and a great deal of the fine detail of the aging of the brain has yet to be robustly cataloged. The relative importance of different forms of damage and dysfunction are not well established in many cases. It is challenging to make that sort of determination given the many interacting forms of degeneration that combine to cause dementia in old age, but results such as those presented here are nonetheless intriguing.

Leaky capillaries in the brain portend early onset of Alzheimer's disease as they signal cognitive impairment before hallmark toxic proteins appear. This finding could help with earlier diagnosis and suggest new targets for drugs that could slow or prevent the onset of the disease. A five-year study, which involved 161 older adults, showed that people with the worst memory problems also had the most leakage in their brain's blood vessels - regardless of whether abnormal proteins amyloid and tau were present. In healthy brains, the cells that make up blood vessels fit together so tightly they form a barrier that keeps stray cells, pathogens, metals, and other unhealthy substances from reaching brain tissue. Scientists call this the blood-brain barrier. In some aging brains, the seams between cells loosen, and the blood vessels become permeable.

Participants in the study had their memory and thinking ability assessed through a series of tasks and tests, resulting in measures of cognitive function and a clinical dementia rating score. Individuals diagnosed with disorders that might account for cognitive impairment were excluded. The researchers used neuroimaging and cerebral spinal fluid analysis to measure the permeability, or leakiness, of capillaries serving the brain's hippocampus, and found a strong correlation between impairment and leakage. "The results were really kind of eye-opening. It didn't matter whether people had amyloid or tau pathology; they still had cognitive impairment."

Link: https://news.usc.edu/153475/usc-alzheimers-research-leaky-capillaries/

Accelerated Bone Regeneration via Transplant of Engineered Perivascular Stem Cells

Reprogramming stem or progenitor cells to adjust their behavior is growing in popularity as an approach to regenerative medicine. The large reductions in the cost of exploring cellular mechanisms achieved over the past twenty years mean that there is now a much greater understanding of relevant mechanisms, as well as a greater capacity to discover novel targets of interest for specific goals in altered cell behavior. The more straightforward outcome in this part of the field is simply to increase stem cell activity, to reduce the amount of time these cells spend quiescent rather than actively supplying tissue with new daughter somatic cells to assist in repair. As today's open access paper illustrates, there are certainly other options on the table, however.

Many stem cell populations are multipotent, meaning that they are capable of generating several different types of somatic cell. If only one type is desired for regeneration, then steering the stem cells into creating only that type for a while is effectively the same thing as speeding up their activity in general. Researchers here do this for cells that create both fat and bone tissue, identifying a regulatory protein, WISP1, that determines which is produced. These cells can then be harvested, engineered to express a higher level of WISP1, and used as a cell therapy to accelerate bone regrowth. That, at least, is the hope, given the initial evidence here from an animal study.

Stem Cell Signal Drives New Bone Building

Stem cells have the potential to develop into a variety of cell types including those that make up living tissues, such as bones. Scientists have long sought ways to manipulate the growth and developmental path of these cells, to repair or replace tissue lost to disease or injury. Previous studies showed that a particular type of stem cell - perivascular stem cells - had the ability to become either bone or fat, and that the protein WISP-1 plays a key role in directing these stem cells.

In a new study, researchers engineered stem cells collected from patients to block the production of the WISP-1 protein. Looking at gene activity in the cells without WISP-1, they found that four genes that cause fat formation were turned on 50-200 percent higher than control cells that contained normal levels of the WISP-1 protein. The team then engineered human fat tissue stem cells to make more WISP-1 protein than normal, and found that three genes controlling bone formation became twice as active as in the control cells, and fat driving genes such as peroxisome proliferator-activated receptor gamma (PPARγ) decreased in activity in favor of "bone genes" by 42 percent.

The researchers next designed an experiment to test whether the WISP-1 protein could be used to improve bone healing in rats that underwent a type of spinal fusion. The researchers mimicked the human surgical procedure in rats, but in addition, they injected - between the fused spinal bones - human stem cells with WISP-1 turned on. After four weeks, the researchers studied the rats' spinal tissue and observed continued high levels of the WISP-1 protein. They also observed new bone forming, successfully fusing the vertebrae together, whereas the rats not treated with stem cells making WISP-1 did not show any successful bone fusion during the time the researchers were observing.

WISP-1 drives bone formation at the expense of fat formation in human perivascular stem cells

The vascular wall within adipose tissue is a source of mesenchymal progenitors, referred to as perivascular stem/stromal cells (PSC). Those factors that promote the differentiation of PSC into bone or fat cell types are not well understood. Here, we observed high expression of WISP-1 among human PSC in vivo, after purification, and upon transplantation in a bone defect. Next, modulation of WISP-1 expression was performed, using WISP-1 overexpression, WISP-1 protein, or WISP-1 siRNA. Results demonstrated that WISP-1 is expressed in the perivascular niche, and high expression is maintained after purification of PSC, and upon transplantation in a bone microenvironment.

In vitro studies demonstrate that WISP-1 has pro-osteogenic/anti-adipocytic effects in human PSC, and that regulation of BMP signaling activity may underlie these effects. In summary, our results demonstrate the importance of the matricellular protein WISP-1 in regulation of the differentiation of human stem cell types within the perivascular niche. WISP-1 signaling upregulation may be of future benefit in cell therapy mediated bone tissue engineering, for the healing of bone defects or other orthopedic applications.

Suppression of Neural Plasticity in the Visual Cortex Reversed in Adult Mice

Researchers here identify a mechanism that suppresses neural plasticity in the visual cortex of adult mice, a part of the developmental process that permits greater plasticity in childhood, but then restricts it in adults. This plasticity is the generation and integration of new neurons into neural circuits. Increased plasticity in adults may be beneficial, allowing for better maintenance and regeneration in the aging brain. That benefit must be balanced against whatever functional reason has led evolution to establish diminished plasticity with advancing age. If resistance to cancer is the answer, similar to the explanation for reduced stem cell function throughout the body in later life, then this can be addressed along the way. If there are other functional reasons for lower levels of plasticity in adults, and thus increased plasticity might damage the adult brain in some way, such as by causing disarray in established neural networks, then this will be more challenging to resolve.

The human brain is very plastic during childhood, and all young mammals have a critical period when different areas of their brains can remodel neural connections in response to external stimuli. Disruption of this precise developmental sequence results in serious damage; conditions such as autism potentially involve disrupted critical periods. "It's been known for a while that maturation of inhibitory nerve cells in the brain controls the onset of critical period plasticity, but how this plasticity wanes as the brain matures is not understood. We've had some evidence that a set of molecules called SynCAMs may be involved in this process, so we decided to dig deeper into those specific molecules."

The study focused on the visual cortex, the part of the brain responsible for processing visual scenes, in which plasticity has been examined in many species. The researchers were able to measure activity of neurons in awake mice freely responding to visual stimuli. They found that removal of the SynCAM 1 molecule from the brain increased plasticity in the visual cortex of both young and adult mice. Further research found that SynCAM 1 controls a very specific type of neuronal connection termed synapses: the long-distance synapses between the visual thalamus, located beneath the cerebral cortex, and inhibitory neurons in the cortex. SynCAM 1 was found to be necessary for the formation of synapses between thalamus and inhibitory neurons, which in turn helps inhibitory neurons to mature and actively restrict critical period plasticity.

The researchers liken inhibitory neurons to a dial controlling when brain plasticity can occur. Plasticity is needed during early development, as the function of different brain areas matures. Mature function is then cemented into place by molecules like SynCAM 1. "Therefore, the limited ability of the mature brain to change is not simply a consequence of age but is directly enforced by the SynCAM 1 mechanism. This allows us to target the mechanism to re-open plasticity in the mature brain, which could be relevant for treating disorders like autism. Combined with the latest approaches in genetic manipulation, this may prove to be a new path to tackle both childhood disorders and brain injury in adults."

Link: https://now.tufts.edu/news-releases/brain-plasticity-restored-adult-mice-through-targeting-specific-nerve-cell-connections

MANF Declines with Age and is Required for Parabiosis Benefits to the Liver

Researchers have identified MANF as a factor responsible for at least some of the benefits provided to the older of two animals with linked circulatory systems. Joining two animals, usually mice, in this way is known as parabiosis. It has been used a tool to explore the role of the signaling environment of blood and tissues in aging. Stem cell function, for example, declines with age, and a sizable part of that decline appears to be a reaction to the changing, damaged environment rather than inherent damage in the stem cells themselves. Thus signals must exist to mediate the altered behavior of cells in response to what is going on around them.

If signals exist, then they can be overridden. Some research groups are searching for factors in young blood that might be used to boost stem cell function and tissue function in old mice. Other groups are convinced that the effect is due to dilution of harmful factors in old blood rather than the addition of helpful factors in young blood. The evidence on both sides is compelling, and the conflicts are yet to be resolved. While that debate is ongoing, it seems reasonable to expect further discoveries of signals and regulators that can increase stem cell activity in old tissues to some degree. That tends to help spur greater tissue maintenance and repair, but with some presently unknown additional cancer risk as damaged cells are forced back to work.

Older mice who are surgically joined with young mice in order to share a common bloodstream get stronger and healthier, making parabiosis one of the hottest topics in age research. Researchers report that MANF (mesencephalic astrocyte-derived neurotrophic factor) is one of the factors responsible for rejuvenating the transfused older mice. Researchers also show the naturally-occurring, evolutionarily-conserved repair mechanism protects against liver damage in aging mice and extends lifespan in flies.

While researchers have yet to understand why MANF levels decrease with age, MANF deficiency has obvious hallmarks. Flies genetically engineered to express less MANF suffered from increased inflammation and shorter lifespans. MANF-deficient mice had increased inflammation in many tissues as well as progressive liver damage and fatty liver disease. Older mice who shared blood with MANF-deficient younger mice did not benefit from the transfusion of young blood.

"MANF appears to regulate inflammatory pathways that are common to many age-related diseases. We are hoping its effects extend beyond the liver, we plan to explore this in other tissues. The search for systemic treatments that would broadly delay or prevent age-related diseases remains the holy grail of research in aging. Given that MANF appears to modulate the immune system, we are excited to explore the larger implications of its therapeutic use. We are also cautious. There are many tissues and organ systems to evaluate in terms of MANF and we have yet to determine its effects on lifespan in the mouse."

Link: https://www.buckinstitute.org/news/manf-identifed-as-a-rejuvenating-factor-in-parabiosis/

Nattokinase and Reversal of Atherosclerotic Lesions

Atherosclerosis is one of the great killers. Fatty deposits form in blood vessels walls, narrowing and weakening the vessels. Eventually something ruptures, and the result is a stroke or heart attack, but even absent that the condition can narrow vessels sufficiently to cause fatal coronary artery disease. Even with modern medicine, the condition is inexorable: the toolkit doesn't yet include a way to more than slightly reverse the buildup of these plaques, and medical professionals must focus on ways to incrementally slow the progression of atherosclerosis rather than delivering any true cure.

One of the side-effects of starting a company, Repair Biotechnologies, that is working on a way to reverse atherosclerotic plaque is that I've been doing a great deal more reading on the topic of atherosclerosis than I would otherwise have done in the course of writing Fight Aging! Thus I turn up interesting items from the past few years that I missed at the time because I lacked the context to understand why they were worthy of notice, or just didn't have the sort of focus on atherosclerosis that I have at the moment. The papers I'll share today fall into this category, providing evidence for nattokinase, a very simple and readily available supplement, to have a surprisingly large effect on atherosclerotic lesions in humans. After six months of treatment, a third of the lesions were removed.

A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia

All enrolled patients were from the Out-Patient Clinic of the Department of TCM at the 3rd Affiliated Hospital of Sun Yat-sen University. Using randomised picking method, all patients were randomly assigned to one of two groups, nattokinase (NK) and statin (ST) group. NK Group-patients were given NK at a daily dose of 6000 FU and ST Group-patients were treated with statin (simvastatin 20 mg) daily. The treatment course was 26 weeks. Common carotid artery intima media thickness (CCA-IMT), carotid plaque size and blood lipid profile of the patients were measured before and after treatment.

A total of 82 patients were enrolled in the study and 76 patients completed the study. Following the treatments for 26 weeks, there was a significant reduction in CCA-IMT and carotid plaque size in both groups compared with the baseline before treatment. The carotid plaque size and CCA-IMT reduced from 0.25±0.12cm2 to 0.16±0.10cm2 and from 1.13±0.12mm to 1.01±0.11mm, repectively. The reduction in the NK group was significantly profound, a 36.6% reduction in plaque size in NK group versus 11.5% change in ST group. Both treatments reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG).

Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases

Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of Natto has been linked to a reduction in cardiovascular disease mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects. This review covers the major pharmacologic effects of NK with a focus on its clinical relevance to cardiovascular disease.

This effect size on atherosclerotic lesions is big enough to be suspicious, given that nattokinase is a supplement in common use, and the dose used is not outrageously large. We seem to be seeing a lot of that sort of thing these days, however; sometimes significance goes unnoticed, but equally sometimes it is an issue with the study that will be corrected later. It is hard to tell which without meaningful further effort. Does bisphosphonate treatment actually extend life expectancy by five years, and did this really did go unnoticed despite its widespread use in older people? Is fisetin actually a significantly effective senolytic compound in humans despite being widely used; did the very high senolytic dose in comparison to the usual supplement dose successful hide this property? How did nearly twenty years of earnest development and use of they chemotherapeutic dasatinib go past without anyone noticing that it killed enough senescent cells to improve health and measures of aging in mice and people? And so forth.

Over the past few decades, hundreds of millions of dollars (at the very least) have been spent on clinical trials to try to reverse atherosclerosis - to give existing repair systems in the body sufficient breathing space or increased capacity, allowing them to break down the fatty deposits that form in blood vessels. The sponsors of any of those trials would have been ecstatic to find a reliable reversal of atherosclerotic plaque that was half the size of that noted in the nattokinase trial here. One might take a look at a 2012 review paper that surveys the degree to which treatments at the time could achieve the goal of reversing atherosclerosis. A reversal of 15-20% in an unreliable fraction of patients was about the best that could be done. Most approaches were considerably less effective than that. Not a lot has changed in this high level picture since then.

At present the dominant approach to treatment of atherosclerosis is reduction of blood cholesterol, the cholesterol attached to LDL particles, or LDL-C. Statins are the long-standing approach, and are now being joined by even more effective treatments such as PCSK9 inhibitors. This slows down atherosclerosis by (a) lowering overall cholesterol, and thus freeing up some fraction of the macrophage cells that would otherwise have had to shovel it out of blood vessel walls, but more importantly (b) lowering oxidized cholesterol, which is very damaging to macrophages. When considering atherosclerosis and its treatments it is important to consider macrophages: they are drawn to the fatty lesions, and their task once there is to mine cholesterol from the lesion, ingest it, and hand it off to HDL particles that carry it back to the liver for excretion. This is called reverse cholesterol transport.

Atherosclerosis exists because macrophages become overwhelmed, mostly by oxidized cholesterol, but also by sheer volume of cholesterol, or by an overly inflammatory environment. They become agitated, call for help, become foam cells (some of which become senescent, causing further issues) or die. Most of a plaque is made up of the debris of dead macrophages, and the plaque itself is a self-expanding disaster area that calls ever more macrophages to their doom. Reducing the LDL-C slows down this feedback loop, but it cannot do much for existing plaques. There is some regression (the aforementioned 15-20% at best) because macrophages are given some breathing room, but plaques continue to grow at the new slower pace, and people continue to die.

There has been a considerable amount of work undertaken over the years on alternatives to lowering LDL-C. Researchers have tried all sorts of ways to improve the ability of macrophages to mine cholesterol and send it back to the liver. They have tried increased numbers of HDL particles (which are formed from APOA1 protein). They have tried altered forms of APOA1 found in some human populations that are associated with lower levels of atherosclerosis. They have tried the introduction of artificial HDL particles to swell the numbers. They have tried upregulation of the ABCA1 and ABCG1 proteins that perform the actual handoff of cholesterol molecules to APOA1. There is more in the same vein.

All of these things work pretty well in mice; the current best approaches produce 50% reversion of atherosclerotic lesions in animal studies. Yet all of those tried in humans, meaning the HDL and APOA1 approaches, have failed miserably in clinical trials. What this means is that there is something that the research community doesn't yet understand in the low-level detailed differences between human and mouse reverse cholesterol transport. That is a big roadblock for anyone turning up to propose some form of enhanced cholesterol transport as a therapy, even if intending to try one of the varied effective-in-mice approaches that hasn't yet been trialed in humans.

In this context, one can see that evidence for a common supplement to manage 36% reversion of lesions in humans is both welcome and jarring. It will certainly have to be replicated before many researchers in the LDL-C-focused side of the scientific community are likely to take it all that seriously. Any simple, easily obtained improvement should be welcome. Nonetheless, it is still only reversion by a third. The disease will still progress, and will still kill people. The research community has to do better than this.

The Second Ending Age-Related Diseases Conference will be Held in July 2019

The second Ending Age-Related Diseases conference, hosted by the Life Extension Advocacy Foundation (LEAF) staff and volunteers, will be held in New York this coming July. It will bring together entrepreneurs, investors, and researchers to discuss progress towards bringing aging under medical control, and thus creating true cures for age-related conditions. I attended last year's inaugural conference in the series, and recommend it. LEAF puts on a good conference, so consider registering.

After the incredible success of the conference Ending Age-Related Diseases 2018, the Life Extension Advocacy Foundation is happy to announce its second annual conference, Ending Age-Related Diseases 2019, which is to be held at Cooper Union in New York City on July 11-12th, 2019. The conference is aimed at focusing the NYC business community's attention on the current state of aging and rejuvenation research that has the potential to prevent and cure age-related diseases. With multiple research projects targeting the underlying processes of aging in order to develop preventive medicines, promoting collaboration between academia, the rejuvenation industry, and investors becomes an increasingly important task.

The list of confirmed speakers already includes renowned researchers and visionaries, such as Dr. Aubrey de Grey (SENS Research Foundation), Michael Greve (KIZOO Technology Ventures, Forever Healthy Foundation), Dr. Vadim Gladyshev (Harvard Medical School), Dr. Vera Gorbunova (University of Rochester), Dr. Alex Zhavoronkov (Insilico Medicine), and Reason and Bill Cherman (Repair Biotechnologies), with more speakers from rejuvenation biotechnology companies and the investment sector to be confirmed soon.

"This year's conference will focus on two main topics. The first topic will be progress in aging research, from fundamental studies to the interventions that are being tested in human clinical trials and the development of reliable biomarkers of aging. The second topic will be devoted to the hurdles of implementing these emerging rejuvenation biotechnologies into clinical practice, with a special focus on investment, the regulatory landscape, and the preparedness of the medical community. This way, we hope not only to attract the attention of investors to these very promising medical innovations but also to promote public dialogue on how to ensure their availability and accessibility to our aging society."

Link: https://www.leafscience.org/nyc2019-pr/

Versican May Increase Cellular Senescence and Calcification in the Blood Vessels of Hyperglycemic Patients

I found this paper quite intriguing, as it links together a number of themes in vascular aging and the similar forms of vascular dysfunction seen in metabolic syndrome and diabetes. The molecular damage of aging in blood vessel walls causes stiffness of blood vessels, which in turn causes hypertension. This is one of the more important means by which low level biochemical damage is translated to high level structural damage to tissues, as raised blood pressure causes all sorts of harm. The damage that leads to vascular stiffness includes (a) cross-linking, in which sugary metabolic byproducts form links between molecules of the extracellular matrix, impeding its elasticity, (b) calcification, in which cells begin to inappropriately deposit calcium into the extracellular matrix, also degrading elasticity, and (c) failure of the vascular smooth muscle cells to perform appropriately when constricting or dilating blood vessels.

This last item has a number of poorly mapped underlying causes, but chronic inflammation appears to be a contributing issue. Chronic inflammation is also implicated in calcification. Chronic inflammation is one of the downstream consequences of cellular senescence, and there is evidence for the presence of senescent cells to be involved in calcification in blood vessel walls. So these items are already quite well connected together. The paper here closes the loop further by finding a form of intracellular signaling that is likely present in hyperglycemic individuals, who also exhibit raised levels of cross-linking, that spurs the formation of more senescent cells in blood vessel walls. Hyperglycemia is just the excessive case: everyone who consumes the usual modern amount of dietary sugar is probably in an incrementally worse position over the long term than people who consume less sugar, due to this and related mechanisms.

A major determinant of vascular aging is vascular calcification, characterized by vascular smooth muscle cells (VSMCs) calcification. Transdifferentiation of VSMCs into osteoblasts is considered to be the most critical pathophysiological of VSMCs calcification. There is accumulating evidence suggesting that VSMCs calcification/senescence have central roles in the development and progression of diabetes-related cardiovascular disorders.

The vascular response to hyperglycemia is a multifactorial process involving endothelial cells (ECs) and VSMCs, although the mechanism by which the information in circulating blood are transferred from ECs to VSMCs is yet to be understood. Signaling between ECs and VSMCs is crucial for the pathogenesis of diabetic vascular calcification/aging. However, how does circulating high glucose affect the calcification/senescence of VSMCs that are not directly contact with the blood? Exosomes, small vesicles with a diameter of 40-100 nm released from various cell types, have gained much attention for their role in intercellular communication. Exosomes can transfer active proteins, lipids, small molecules, and RNAs from their cell of origin to the target cell. ECs have been demonstrated to secrete exosomes, and the transfer of signaling molecules by exosomes may thus provide a way for communicating between ECs and VSMCs. Similarly, prior study has demonstrated that exosomes from senescent ECs promotes VSMCs calcification.

Exosomes from human umbilical vein endothelial cells (HUVEC-Exos) were isolated from normal glucose (NG) and high glucose (HG) stimulated HUVECs (NG/HG-HUVEC-Exos). Exosomes isolated from HG-HUVEC-Exos induced calcification/senescence in VSMCs. HG-HUVEC-Exos significantly increased lactate dehydrogenase (LDH) activity, as well as the product of lipid peroxidation, and decreased oxidative stress marker activity, as compared with NG-HUVEC-Exos. Moreover, mechanism studies showed that mitochondrial membrane potential and the expression levels of mitochondrial function related protein HADHA and Cox-4 were significantly decreased in HG-HUVEC-Exos compared to controls. Proteomic analysis showed that HG-HUVEC-Exos consisted of higher level of versican (VCAN), as compared with NG-HUVEC-Exos.

VCAN is mainly localized to the mitochondria of VSMCs. Knockdown of VCAN with siRNA in HUVECs, inhibited HG-HUVEC-Exos-induced mitochondrial dysfunction and calcification/senescence of VSMCs. Our data suggest a functional role for VCAN inside VSMCs. VCAN carried by HG-HUVEC-Exos promotes VSMCs calcification/senescence, probably by inducing mitochondrial dysfunction. Since VSMCs calcification/senescence could induce vascular dysfunction, blockage of the exosome-mediated transfer of VCAN between these two cells may serve as a potential therapeutic target against diabetic vascular complications. More work will be needed to explore this possibility and to better understand the intracellular roles of VCAN.

Link: https://doi.org/10.1186/s13578-018-0263-x

Impressions from the January 2019 Juvenescence Gathering

The JP Morgan Healthcare conference took place in San Francisco this past week. The conference is less interesting in and of itself, but it is the spur for any number of other short gatherings of various biotech investment and business interest groups. So in the middle of last week, Jim Mellon and the other Juvenescence principals were in town to host their second annual showcase for startups working on aging, and the BioAge and Felicis Ventures folk hosted the overlapping Extending Human Lifespan event on the same day. I had to miss that second one, as I was presenting Repair Biotechnologies at the Juvenescence event to a small crowd of other entrepreneurs, angel investors, and venture capitalists of varied allegiances, and stayed for the whole event to see the other presentations.

Many of our fellow travelers associated with SENS rejuvenation research and Methuselah Foundation spheres were present to meet and greet: the SENS Research Foundation folk; much of the Oisin Biotechnologies team; Doug Ethell of Leucadia Therapeutics; Frank Schüler of Forever Healthy Foundation; a number of angel investors I've interacted with in the past while we were interested in the same companies; and many others arriving and leaving as they moved between events.

One thing that caught my eye is that the theme of diversity and new hypotheses in Alzheimer's research (or outright rebellion against the past two decades of relentless focus on clearing amyloid via immunotherapies, present it as you will) has robustly made its way to the commercial development stage. Leucadia Therapeutics were presenting their latest work on ferrets as an animal model to illustrate that the development of Alzheimer's occurs due to blocked drainage of cerebrospinal fluid though the cribriform plate. Related company Enclear Therapies was not present, but was a topic of discussion given that their founders have very similar thoughts on filtration of cerebrospinal fluid. Maxwell Biosciences principals presented their work on the LL-37 antimicrobial peptide as a test of the microbial theories of Alzheimer's disease, in which infection is provoking greater aggregation of amyloid and inflammation to accelerate other aspects of the condition. An attempt at intervention is perhaps the best way to clear up questions of causality here: do we see microbial infections in the Alzheimer's brain because they are an important cause, or because immune dysfunction in general tends to be more advanced in these patients?

A further contingent of startups at the Juvenescence event were similarly of interest for having a good shot at answering scientific questions very much faster than the academic community can, due to the influx of resources from the venture community. Elevian falls into this category, with their work on GDF11. Early work on parabiosis, joining the circulatory systems of an old and young mouse, pointed to GDF11 as a possible factor in conveying benefits to the old mouse. There is now some debate over why parabiosis works, however, casting doubt on the argument of beneficial factors in young blood. Similarly, there has been some back and forth in the research community regarding whether or not past work on GDF11 is as it appears to be, but the Elevian staff claim to have resolved the conflicts. In many cases, the best way to resolve a debate of this nature is to just forge ahead and try to build a therapy; that effort can pull in much greater funding more rapidly than the academic community can manage via the usual channels available to researchers.

Another item that caught my attention, and seems worthy of consideration, is that the infrastructure and drug discovery companies in our space of treating aging as a medical condition are the furthest ahead in terms of building out relationships with venture concerns, obtaining larger funding, and breaking ground on their larger and later projects. This may reflect the focus of groups like Juvenescence from the past couple of years, their approach to establish an initial presence in a field. Examples of this trend include In Silico Medicine and Ichor Therapeutics' portfolio company Antoxerene, both of which offer faster, cheaper discovery of small molecule drugs for any sort of use, but both of which happen to have founders very interested in aging and longevity over and above any of the myriad other uses for their technologies. In Silico Medicine in particular is clearly advancing by leaps and bounds in Asia as they gather support from the high-end venture groups there.

(I'll confess that I've never found the development of lower level biotechnological infrastructure all that interesting as a topic. Obviously it is vital, and acceleration of technological progress is achieved by making common tasks easier, faster, and cheaper. Someone has to do it, invest in it, and focus on it, but that someone will never be me. I am far more interested in specific implementations of rejuvenation therapies, the development groups who might end up using the infrastructure to build a given treatment).

San Francisco is ever a hub of connections for the venture and technology spaces. It is the base of operations and home for a sizable number of high net worth individuals, agents for other high net worth individuals, fund partners deploying sizable amounts of capital, successful founders turned angel investors, successful angel investors turned founders - all rubbing shoulders, bumping into one another at the supermarket, and two degrees of separation removed at most. It is through this very connected network that interest in the biotechnologies of rejuvenation has been spreading these past fifteen years, pushed along by the presence of the SENS Research Foundation in the Bay Area. This occurred slowly at first, given that the focus was initially philanthropic funding of research rather than startups, but much more rapidly these past few years now that the first rejuvenation biotechnology startups are arriving on the scene.

At a small gathering after the Juvenescence event, those attending included an older AI-focused entrepreneur-turned-investor who has a growing interest in biotechnology, and a recently successful young founder from the technology space who is now taking life science classes to get up to speed on what he considers to be his next area of interest. The next day I met with an angel investor who attended the Juvenescence event, and who is cheerfully incorporating biotech companies into his previously tech-company-heavy portfolio. This dynamic is similarly reflected in venture firms such as Y Combinator, Felicis Ventures, and (closer to our community) Kizoo Technology Ventures led by Michael Greve, among others. They are transitioning into biotechnology, and the interest in doing something about aging is a driving motivation for many involved. For others, it is the realization that successful rejuvenation therapies will lead to a market so enormous as to make a pittance of near everything that has come before. Self-interest is a machine to be harnessed in these matters: while fundamental research is very cheap, later commercialization and distribution of medical therapies to millions of patients is enormously expensive. We need the deep pockets to enter this space, and to pull in all of their allies and other interested parties, if we are to see a reasonable rate of progress in moving rejuvenation therapies from lab to clinic.

The only other alternative is some form of major, lasting revolution in the regulatory environment, as that is the dominant cause of cost and delay. Therapies could be brought to market just as safely as they are today at a fraction of the present cost; the majority of cost and time imposed by the FDA, EMA, and the like is entirely unnecessary, some of it the debris of regulatory capture used by larger pharmaceutical entities to suppress competition, some of it the consequences of bureaucrats going to any lengths to avoid negative press, even by the means of preventing most new technologies from ever being approved. I'm certainly in favor of great upheaval in the development of medical therapies, but tearing down the present edifice is a vast project, and arguably one that will be much less costly and difficult to undertake given the existence of the first rejuvenation therapies and the public demand for more.

A final thought on investors and the science of rejuvenation: most of the newcomers are still finding their way to an understanding of the science in this space. They cannot yet tell the difference between projects likely to produce significant gains in human life span, those based on repair of the damage that causes aging, and those that cannot in principle produce large gains, those based on, say, upregulation of stress responses, such as mTOR inhibitors. Investors are guided by potential for financial gains, but that metric is not in fact a great way to tell the difference between better and worse approaches to aging. The typical competently run medical biotechnology company is acquired or goes public before the final determination of effectiveness of their programs; perhaps somewhere just after the first human trial, or even prior to that when the market is hot. Companies can do this after showing marginal benefits, or even just potential for marginal benefits, with a therapy that will never produce large or reliable benefits in larger patient populations, and yet still realize large gains for the early investors. So this is a challenge, and an opportunity for patient advocates to make a difference - to help guide those people chasing gains into obtaining those gains by backing better rather than worse technologies.

Tau Impairs Both Mitochondrial Function and Quality Control

Researchers here show that tau protein, a feature of late stage Alzheimer's disease, causes issues with mitochondrial quality control mechanisms responsible for removing damaged or dysfunctional mitochondria. Since tau also harms the function of mitochondria, this is particularly pernicious, and may be a significant component of the cell death that follows tau aggregation. Mitochondrial dysfunction is a feature of most neurodegenerative diseases, causing cellular processes in the brain to falter for lack of energy, but the question of where it sits in the web of cause and consequence in relation to other disease mechanisms remains to be resolved. Is the case that Alzheimer's tends to occur more readily in people with worse age-related mitochondrial dysfunction, or does one or more of the other aspects of Alzheimer's, such as tau aggregation, produce the observed greater level of mitochondrial dysfunction as a downstream effect? Or both? This sort of question is surprisingly hard to answer in conditions that have many contributing causes.

Accumulation of clumps of tau is a well-established hallmark of Alzheimer's disease and other neurodegenerative disorders, as is the aggregation of damaged mitochondria, the powerhouse of a cell. However, the interaction between tau and mitochondria is still being explored, and new research has found an additional disruptive function of tau in terms of mitochondrial health. "It has long been known that there is an accumulation of abnormal mitochondria in neurodegenerative diseases, including Alzheimer's disease. More specifically, tau has previously been shown to impair different aspects of mitochondrial function, and here, we find that tau also impairs the degradation of mitochondria. This causes a toxic cycle whereby tau both damages mitochondria and then also prevents their removal."

One of the ways by which tau causes cell damage is by preventing the removal of damaged mitochondria, a process referred to as mitophagy. Normally, damaged mitochondria are trafficked to the lysosome (the waste remover of the cell) for destruction, by a molecule called Parkin, which moves from the intracellular fluid to the impacted mitochondria to start the trafficking process. However, researchers found tau impaired this process by interacting "aberrantly" with the Parkin protein in the intracellular fluid before it could reach the mitochondria, thereby preventing the removal process, and with damaging consequences for the cell.

Link: https://qbi.uq.edu.au/article/2018/12/how-alzheimer%E2%80%99s-protein-impairs-brain-cells

PUM2 and MFF in the Dysregulation of Mitochondrial Fission in Aging

Mitochondria, the power plants of the cell, become dysfunctional over the course of aging. This is a general process in all mitochondria, and not the same thing as the severe mitochondrial DNA damage that occurs in only a few cells, but that has a widespread detrimental effect. In this more general mitochondrial malaise, there are changes in shape and important functions decline; energy-hungry tissues such as brain and muscle suffer as a consequence.

Mitochondria are the descendants of ancient symbiotic bacteria, and thus act much like bacteria in carrying out fission and fusion, and passing component parts around between one another. In recent years, researchers have found that imbalances between fission and fusion appear in aging, this impairs the ability of autophagic processes to remove damaged mitochondria, and that provoking more fission or less fusion slows aging in short-lived species. Researchers continue to investigate the mechanisms underlying this imbalance; the results noted here are an illustrative example of the progress taking place in this part of the field.

Mechanisms based on mRNA transcription, a very important step in gene expression, are a part of the complex regulatory mechanisms in our cells. RNA-binding proteins (RBPs) bind mRNA molecules and regulate their fate after gene transcription. In this study, scientists screened cells from old animals to identify any RBPs that change upon aging. The screening showed that one particular protein, Pumilio2 (PUM2), was highly induced in old animals. PUM2 binds mRNA molecules containing specific recognition sites. Upon its binding, PUM2 represses the translation of the target mRNAs into proteins.

Using a systems genetics approach, the researchers then identified a new mRNA target that PUM2 binds. The mRNA encodes for a protein called Mitochondrial Fission Factor (MFF), and is a pivotal regulator of mitochondrial fission - a process by which mitochondria break up into smaller mitochondria. Having high levels of MFF also allows the clearance of broken up, dysfunctional mitochondria, a process called mitophagy.

The study found that this newly identified PUM2/MFF axis is dysregulated upon aging. Evidence for this came from examining muscle and brain tissues of old animals, which were found to have more PUM2, and, consequently, fewer MFF proteins. This leads to a reduction of mitochondrial fission and mitophagy, and without the ability to chop up and remove smaller mitochondria, the aged tissues start accumulating bigger and unhealthy organelles.

But removing PUM2 from the muscles of old mice can reverse this. "We used the CRISPR-Cas9 technology to specifically target and inactivate the gene encoding for Pum2 in the gastrocnemius muscles of old rodents. Reducing Pum2 levels, we obtained more MFF protein and increased mitochondrial fragmentation and mitophagy. Notably, the consequence was a significant improvement of the mitochondrial function of the old animals."

Link: https://actu.epfl.ch/news/targeting-an-rna-binding-protein-to-fight-aging/

Old Tissues Have Many Mutations, Even Absent Cancer

Cancer is the result of random mutational damage to nuclear DNA, but most such damage has no real effect, not even to the behavior of the affected cell. Cells in old tissues are riddled with mutations, but it is an open question as to how much this accumulated damage contributes to aging beyond cancer risk. Does it produce sufficient disarray in tissue function to be measured? A mutation capable of meaningfully altering cell behavior (a small subset of all possible mutations) can only have a noticeable affect when it occurs in many cells, a significant fraction of those present in a tissue. One slightly defective cell is a drop in the ocean, provided it isn't actively cancerous.

Many researchers consider that the outcome of clonal expansion of mutations in adult tissue can be achieved when the original mutation occurs in a stem cell of some kind. The mutation can spread with the long-term delivery of a supply of daughter somatic cells and their descendants. Along these lines, the studies noted in the article below raise the possibility that cancer-associated mutations can also grant this ability to spread through excessive replication, yet without immediately resulting in the production of a tumor.

The field lacks definitive studies and models that would enable researchers to put numbers to the contribution of mutational damage to degenerative aging and age-related diseases other than cancer. Clearly the boundary between production of cancer and production of functional damage isn't sharply drawn if expansion of mutations is a feature of the pre-cancerous state. Fixing the damage is usually the best way to proceed when answering this sort of question, but that is very hard to achieve for random DNA damage in isolation of all the other aspects of aging. Every cell needs custom work. More practically, delivering newly created, undamaged stem cell populations to replace old stem cell populations is a feasible form of future therapy, but it certainly doesn't isolate DNA damage as the only altered variable.

Mutations differ in normal and cancer cells of the oesophagus

Errors in DNA replication can alter a cell's DNA sequence. If such alterations occur early enough in embryonic development, the changes are inherited by all of an organism's cells. But if the alterations arise later in adult life, it is more difficult to track such changes in a small number of cells in a specific tissue, so the extent of these alterations in normal tissues is poorly understood. It is thought that cancer is initiated when cells acquire a minimum compendium of genetic alterations needed to trigger tumour formation. Understanding when such initiating mutations occur in normal cells is crucial for enabling reconstruction of the early events that lead to cancer.

Researchers have analysed the extent of mutations in human epithelial tissue from the healthy oesophagus, and how this relates to the processes that drive cancer development. They sequenced 74 cancer-associated genes in 844 tissue samples taken from the upper oesophagus of 9 healthy donors who differed in gender, age and lifestyle. For 21 of these samples, the authors also determined whole-genome sequences. A previous study assessing mutations in healthy skin cells reported between two and six mutations per million nucleotides of DNA. By contrast, here the mutations in oesophageal cells arose at a roughly tenfold lower rate. This difference is unsurprising, because skin cells are exposed to more DNA-damaging agents, such as ultraviolet light, than are oesophageal cells.

Instead, the surprise is that, compared with healthy skin, the healthy oesophagus has more mutations in cancer-associated genes. Moreover, at least a subset of these altered genes was under strong positive selection, meaning that the genetic alterations promoted cell proliferation, leading to the formation of cell clones. Compared with the samples from younger people, the overall number of mutations, the number of mutations in cancer-associated genes and the size of the clones were all greater in the samples from older people. The authors found that the donors' samples had an average of about 120 different mutations in NOTCH1, a known cancer-associated gene, per square centimetre of normal oesophageal tissue.

The clonal expansion of normal oesophageal cells after cancer-promoting genes have mutated seems to be necessary, but not sufficient, to drive cancer, so something else must happen to the cells for tumours to form. For example, gaining a large-enough number of alterations in cancer-promoting genes might be needed. Few of the mutations were present in all the cells of the normal clones, and many of the cancer-promoting mutations were often found in spatially distinct subclones. This suggests that none of the normal cells had acquired enough cancer-promoting alterations to start cancer formation.

More on TREM2 and Immune Function in Alzheimer's Disease

You might recall research published early last year on TREM2 as a possible regulator of immune cell clearance of amyloid in Alzheimer's disease. Researchers here provide a further update on their investigations of the role of TREM2 in this process. To the degree that the immune system falters in this task of clearing metabolic waste with age, and to the degree that this issue can be reversed or overridden, this may prove to be a useful approach to age-related protein aggregates in the brain, and their contribution to neurodegenerative disease. As is so often the case, however, a treatment cannot be immediately and straightforwardly constructed based on manipulation of TREM2. Its relationship with immune cell activity and the Alzheimer's disease state is complex.

A hallmark of Alzheimer's disease is the formation of toxic deposits in the brain, so-called plaques. Specialized immune cells termed microglia protect the brain by clearing it from these toxic debris. TREM2 is a key factor in activating microglia and thus serves as an important target for novel therapeutic approaches. To further explore these therapeutic options, scientists undertook a detailed analysis of disease development in mice with and without a functional TREM2 gene.

In mice with healthy TREM2, microglia cluster around small emerging plaques early in the disease process and prevent them from enlarging or spreading. Researchers were able to show that microglia are specifically attracted to amyloid plaques. They surround individual plaques and engulf them piece by piece. In contrast, in mice lacking TREM2, microglia were unable to carry out this important task. Therapeutic activation of TREM2 in an early stage of the disease could thus help counteract the formation of toxic amyloid-beta protein aggregates.

However, the study results also call for caution when implementing such a therapy. While TREM2 prevents plaque formation early in disease progression, it may have the opposite effect later on. In more advanced stages of the disease, the plaques grew faster in mice with functional TREM2 than in mice lacking the corresponding gene. The researchers discovered that this could be explained by the fact that TREM2 induces microglia to produce a substance called ApoE, which enhances aggregate formation. "Our study shows that we have to be extremely careful and investigate a new therapeutic approach thoroughly in animal models before testing it on humans. According to our findings, it could have dramatic consequences if we over-activate microglia. In the future, it will be important to treat Alzheimer's disease in a stage-specific manner."

Link: https://www.dzne.de/en/news/public-relations/press-releases/press/detail/defective-immune-cells-in-the-brain-cause-alzheimers-disease/

Declining Autophagy Implicated in Tau Aggregation in the Aging Brain

Tau aggregation, the formation of solid deposits of altered tau protein called neurofibrillary tangles, is thought to be the most damaging of the processes underlying Alzheimer's disease. The earlier accumulation of amyloid-β only sets the stage for the later accumulation of altered tau. When looking at why protein aggregates such as amyloid-β and tau accumulate only in later life, one of many candidate mechanisms is the decline of autophagy that takes place with aging. Autophagy is the name given to a collection of cellular maintenance processes responsible for clearing out damaged structures and other unwanted waste, such as protein aggregates. A range of interventions shown to slow aging in laboratory species involve raised levels of autophagy: if cells are more aggressively maintained, there is less of a chance for damage and dysfunction in cellular processes to spread and cause further harm. The other side of the coin is that lower levels of autophagy mean more metabolic waste, more damaged components, and more downstream consequences.

Early in the course of Alzheimer's disease, neurons in the brain become clogged with toxic tau proteins that impair and eventually kill the neurons. A new study found that tau accumulates in certain types of neurons, probably because the cellular housekeeping system of autophagy is less effective in these neurons. Researchers have long known that neurodegenerative diseases like Alzheimer's affect some neurons but not others, even leaving neighboring neurons unharmed. But the reasons for this selectivity have been difficult to identify.

The new study was only possible because of new techniques that allow researchers to probe individual cells in the brain. Researchers detected signs that the components of a cellular cleaning system were less abundant in the neurons that accumulate tau proteins. To confirm the connection between the cleaning system and tau buildup, the researchers manipulated BAG3, a regulatory protein in autophagy, in mouse neurons. When the researchers decreased BAG3 levels in mouse neurons, tau piled up. But when BAG3 expression was enhanced, the neurons were able to rid themselves of excess tau.

The researchers have tantalizing, still unpublished data that the same housekeeping deficiencies found in vulnerable neurons occur with aging, which might explain the link between advanced age and Alzheimer's disease. "If we can develop therapies to support these natural defense mechanisms and stop tau from accumulating, then we might be able to prevent, or at least slow, the development of Alzheimer's and other tau-related neurodegenerative diseases."

Link: https://www.cuimc.columbia.edu/news/neurons-good-housekeeping-are-protected-alzheimers

Wary of the Beautiful Fairy Tale of Near Term Rejuvenation

One might compare this interview with researcher Leonid Peshkin to last year's discussion with Vadim Gladyshev. There is a spectrum of caution and pessimism regarding near term progress towards rejuvenation; the pessimists in the research and development communities are not all alike in their viewpoints, and nor do they all have the same take on the complexity of cellular metabolism as a hurdle to progress.

If a researcher thinks that small molecule drugs or gene therapies to alter the operation of metabolism into a state in which aging is slowed are the only way forward, then yes, it is reasonable to consider that progress will be slow and incremental. Metabolism is far from fully mapped, and thus the detailed progression of aging is also full of unknowns. Yet why take the hard path when there is an easier way forward? The whole point of the SENS approach to aging, based upon repair of root cause damage, is to bypass this complexity and lack of knowledge. Remove the known and well-catalogued damage at the root of aging, and a sizable fraction of the consequences will be repaired by the normal processes of tissue maintenance; we know this because we have the example of youthful individuals and their metabolism to draw on.

Of course, it is then possible to debate whether or not the short-term repair projects that can be achieved in the next ten to twenty years will produce large enough gains in life expectancy to enable people to live to see success in the long-term, harder repair projects. Senolytics, breaking of glucosepane cross-links, clearance of protein aggregates, cell replacement therapies, and more, will all be going concerns in the 2020s. But projects such as repair of stochastic mutations in nuclear DNA or damaged nuclear pore molecules in long-lived and critical populations of neurons are well beyond present capabilities.

An Interview with Dr. Leonid Peshkin

As a way of introduction, I'd like to offer a caricature of the currently popular sensationalist view in the field of aging: "We are the chosen generation. Singularity is near. Rejuvenation therapy is almost here. Not one, several a-la-carte: stem cells, factors from young blood, senolytics, Skulachev's ions, NAD, etc. Companies backed up by luminaries from business and science are already sorting out the remaining details, helped by the formidable force of AI technology called 'deep learning'." This fairy tale is beautiful, and deep in my heart, I hope I am mistaken, but I think that at the moment, this positive mysticism is not justified and is rather counterproductive. The excessive optimism is, unfortunately, standing in the way of progress, as I will try to explain.

There are many proposed models of aging, such as the Hallmarks of Aging, SENS, and the deleteriome. Which, if any, of these models do you believe reflects the reality of aging?

I would not want to take part in religious wars. People get very passionate and clash about often vaguely defined terms. Which of the observed hallmarks of aging, from the molecular to the organism levels, are correlates and which are causes of aging is hard to say. Biology has not yet matured to become an exact science. Perhaps owing to my training in quantitative science I take a "model" to mean a level of quantitative understanding that allows for "modeling"; that is, forecasting and answering "what if" questions. Such a model might not be ultimately expressed by a set of crisp human-readable mathematical formulae but rather a large set of tuned parameters in an artificial neural net or some other representation that has not yet been invented. It must, however, provide a way to assess the current state of an organism and predict its lifespan and healthspan in a stable environment, outside of a major perturbation, and then go further to allow for perturbations and adjust the predictions.

Today, I can't even say that there is an agreement in the field of what is a useful definition of "aging". I like "increase of hazard rate (i.e. the probability of dying) with time", which is admittedly a very mathematical notion - precise and not terribly useful. Inverting this formula, we get a curious metaphor - a life without aging can be imagined as a life where, say, once a year, you undergo a treatment that rejuvenates you a year in biological age, or, with some small but non-negligible probability, kills you. Life is a game of chance.

Do you believe that aging is a one-way process or something that is flexible and amenable to intervention?

It is both. Imagine one dramatic intervention: one day, we invent a way to cryo-protect a warm-blooded organism like ours so that it can undergo a freeze-thaw cycle without damage. Now, you are faced with a challenge to design a schedule that determines when, and in what size fractions, you'd like to use up your lifespan. While you are frozen, time stops. While you are alive, you age: the "deleteriome" kicks in, ionizing radiation wrecks your DNA, your defrosted friends and family du jour stress you out, etc. That's what things would look like ad absurdum, illustrating the tradeoffs.

Now, back to the interventions: I imagine a process not unlike a beauty salon, in which you do your nails and hair and get an occasional facelift; all of these are tradeoffs, even if people do not recognize it. Beauty treatments make you look younger at the moment, but cosmetics products may poison your skin and accelerate actual aging. There is evidence of such tradeoffs across organisms in nature; extending lifespan in many species can be accomplished at the expense of reproduction, and in cold-blooded organisms, you can multiply the lifespan several-fold by just cooling the environment down or slowing down metabolic processes in other ways. I believe that the first results will be not so much in giving people free tickets to longer lives but in making the tradeoffs more explicit, educating people and putting them in control of decision making.

Do you consider epigenetic alterations as a cause of aging or a downstream consequence?

Neither cause nor downstream. There is no linear causal chain with the two links of "aging" and "epigenetic alterations"; instead, there are loops and amplifiers in the circuits of aging. Epigenetic alterations have to be caused by something else; these, in turn, control many things. On the other hand, DNA damage is clearly pretty early in the causal network but is hard to undo. There is more hope to proofread and fix "epigenetic alterations". I am very much interested in this direction of research, so much so that we are planning an experiment looking at changes in the distributions of cell types in cell populations that make up young and old individuals. The expectation is that epigenetic alterations lead to de-differentiation and mis-differentiation of cells in old organisms, which could be characterized and further used as end-points for aging interventions.