Fight Aging! Newsletter, March 9th 2015

March 9th 2015

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

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  • Posters for the MILE Demonstration on March 21st
  • Amyloid in the Brains of People Without Alzheimer's Disease
  • Sex Steroid Ablation Spurs Immune System Regeneration
  • More of Brain Aging Than Thought May Be Vascular in Nature
  • What to Expect in Aging
  • Latest Headlines from Fight Aging!
    • The Strategic Focus of Aging Research that Must be Disrupted If We Are to See Greater Progress
    • Demonstrating Enhanced Liver Regeneration in Mice
    • More on Retrotransposons and Aging
    • Considering Nitric Oxide Mechanisms as a Target
    • MOTS-c as Potential Exercise Mimetic
    • Cartilage Regeneration in Rats Using Embryonic Stem Cells
    • Healthy Years Lost to Obesity, Hypertension, and Diabetes
    • When Death is Optional
    • Are Members of Long-Lived Families Healthier?
    • Sitting Time is Associated With Arterial Calcification


The Movement for Indefinite Life Extension (MILE) is one of a number of grassroots initiatives in which ordinary folk like you or I are doing their part to help raise awareness and funding for rejuvenation research. Every great journey is made one small step at a time, and the tipping point at which the public at large begins to accept and supports longevity science in the same way as is the case for cancer research today will be crossed by one such modest effort among many. The community of people who understand and support efforts to bring an end to degenerative aging through medical science grows and diversifies as the years pass. The more of us there are the more that we can do to help advance research and educate the public. There is a role for everyone in this, and at all levels of effort, whether it is donating millions to establish a new research program or persuading a few of your friends that it's pretty silly to be for cancer research but against a cure for all age-related frailty and disease.

MILE is organizing an online demonstration on March 21st to coincide with live meetups in Chicago, Los Angeles, and Washington D.C. I was asked to provide a poster or two, and so bearing in mind that this is a demonstration I ran up something very simple that should be legible at distance. Less is more for this sort of thing, and it is easy enough to cut and paste other taglines and URLs. The font is Liberation Sans Bold, but any generic sans-serif font works just fine at this size.

Support Rejuvenation Research Poster: 4200 x 2800px

Fund More Research Poster: 4200 x 2800px


If surveying what is known of the pathology of age-related conditions, we find an array of cellular damage and metabolic waste accumulation that happens in everyone. The people with age-related medical conditions have a lot more of one or more types of this damage and waste, however. That is the root cause of their dysfunction and frailty. Aging isn't a linear process and damage causes further damage, so small differences early on can always snowball into large differences later. Accumulating damage and waste byproducts as the result of the normal operation of metabolism is common to all of us, and this makes it a good place to look for therapeutic targets. If spending billions and decades on medical research, better to emerge with a treatment that can benefit everyone.

Alzheimer's disease progresses hand in hand with the accumulation of amyloid-β (Aβ) in brain tissues. Much of the comparatively well funded field of Alzheimer's research is focused on clearing amyloid or interfering in the mechanisms thought to link it to cell death and neurodegeneration. There are plenty of other opinions in the field on the relevance of this approach, given that it is proving harder than expected to produce meaningful results in clinical trials, but for now that is where most of the funding goes. This will hopefully produce a technology platform for amyloid clearance, such as via immunotherapies, that can be generalized to clear the other score or so forms of amyloid that accumulate in tissues with advancing age. In some cases it isn't so clear as to exactly what harm they are causing, but they are not present in young tissues in significant amounts, so the prudent course of action is to remove them anyway. Clearance followed by observing the results will probably teach us more about their role in aging than the same amount of time and money spent on more conventional studies.

Amyloid accumulation takes place in everyone, not just those with enough resulting damage to officially qualify as an Alzheimer's patient. The dividing line isn't sharp at all: more amyloid correlates with more cognitive dysfunction, and at some point that tips over the margin. It isn't a road that anyone really wants to be on at all, of course, but nonetheless here we all are until new applications of medical science arrive to rescue us. That will require large amounts of funding and public support, both of which are presently far smaller in scale than they might be. Ours is a society that likes circuses and bonfires in preference to science and progress. When does the damage of aging start? It starts in youth, but takes decades to rise to the point at which it is noticeable. Here are two recent reports of research on this topic:

Alzheimer amyloid clumps found in young adult brains

Scientists examined basal forebrain cholinergic neurons to try to understand why they are damaged early and are among the first to die in normal aging and in Alzheimer's. These vulnerable neurons are closely involved in memory and attention. Researchers examined these neurons from the brains of three groups of deceased individuals: 13 cognitively normal young individuals, ages 20 to 66; 16 non-demented old individuals, ages 70 to 99; and 21 individuals with Alzheimer's ages 60 to 95.

Scientists found amyloid molecules began accumulating inside these neurons in young adulthood and continued throughout the lifespan. Nerve cells in other areas of the brain did not show the same extent of amyloid accumulation. The amyloid molecules in these cells formed small toxic clumps, amyloid oligomers, which were present even in individuals in their 20's and other normal young individuals. The size of the clumps grew larger in older individuals and those with Alzheimer's. "This points to why these neurons die early. The small clumps of amyloid may be a key reason. The lifelong accumulation of amyloid in these neurons likely contributes to the vulnerability of these cells to pathology in aging and loss in Alzheimer's."

Brain Amyloid-β Burden Is Associated with Disruption of Intrinsic Functional Connectivity within the Medial Temporal Lobe in Cognitively Normal Elderly

The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Aβ deposition in preclinical AD, but the pathological relationship between tau and Aβ remains unclear.

We used task-free fMRI with a focus on the medical temporal lobe, together with Aβ PET imaging, in cognitively normal elderly human participants. We found that cortical Aβ load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Aβ load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss.


The immune system is enormously complex and has many jobs. It isn't just a matter of destroying invading pathogens, but also clearing senescent, precancerous, and other unwanted cells. The decline of the immune system in old age is a major contribution to frailty, as not only are the old threatened by infections that the young can shrug off, but the immune system falters in destroying damaged cells that threaten health. The aged immune system falls into a state of ineffectiveness combined with constant overactivity that causes chronic inflammation. Systematic inflammation in turn contributes to the progression of many ultimately fatal age-related conditions. If the immune system could be even partially restored to a more youthful profile, that would go a long way towards improving health in old age.

There are a range of approaches to the problem of immune system aging, not least because there are numerous different contributions to the degeneration of immune function. The supply of new immune cells dries up in later life, leading researchers to propose stem cell therapies, introduction of new immune cells by infusion, or regeneration of the thymus tissues where immune cells mature. Equally the immune system becomes badly misconfigured due to the influence of persistent herpesviruses like cytomegalovirus (CMV). Ever more cells are devoted to uselessly fighting CMV rather than reacting to new threats. Here the direct path to a therapy is to work on ways to selectively destroy the unwanted immune cells, which should prompt the creation of replacements lacking the CMV fixation.

There are plenty of other points at which researchers could intervene by manipulating the processes of immune cell depletion and production, though the effects will probably be less impressive than a sweeping clearance of most unwanted cells. Even fairly simple interventions such as extended fasting have been shown to have some impact, clearing out and then repopulating sections of the immune system for a net benefit. The open access research linked below focuses on tinkering with the regulatory processes that steer creation of immune cells by hematopoietic stem cells in bone marrow, processes called lymphopoiesis and myelopoiesis that are balanced in youth but shift towards increasing myelopoiesis with aging. Like much of this research it is presented in the context of cancer treatments, as the most widely used therapies are hard on the immune system and the cancer community is in search of ways to compensate, but it may have broader implications over the long term for the treatment of immune system decline in aging:

Enhanced Hematopoietic Stem Cell Function Mediates Immune Regeneration following Sex Steroid Blockade

One key etiological factor underlying a wide range of diseases is the progressive decline in immune function with age. At its core is a reduction in lymphopoiesis within the bone marrow (BM) and thymus, attributed in part to a decrease in the number and function of lymphoid progenitors. Increasing evidence suggests that intrinsic changes to the earliest hematopoietic stem cells (HSCs) also contribute toward age-related immune degeneration. Deficiency in DNA repair, altered DNA methylation patterns, aberrant metabolism and reactive oxygen species, and skewed upregulation of myeloid- (at the expense of lymphoid-) associated genes all contribute to altered HSC function with age. However, in addition to intrinsic functional changes, extrinsic alterations to the HSC niche also likely to contribute toward the degeneration of HSC function with age.

Evidence suggests that sex steroids play at least some role in age-related degeneration of lymphopoiesis, and we, and others, have previously shown that sex steroid ablation (SSA) is able to rejuvenate aged and immunodepleted BM and thymus, enhance peripheral T and B cell function, and promote immune recovery following hematopoietic stem cell transplantation. However, the mechanisms underlying SSA-mediated immune regeneration are still unresolved. In this study, we sought to examine the events upstream of SSA-mediated lymphoid regeneration, focusing on the earliest HSPCs.

We herein show that, mechanistically, SSA induces hematopoietic and lymphoid recovery by functionally enhancing both HSC self-renewal and propensity for lymphoid differentiation through intrinsic molecular changes. Our transcriptome analysis revealed further hematopoietic support through rejuvenation of the bone marrow (BM) microenvironment, with upregulation of key hematopoietic factors and master regulatory factors associated with aging such as Foxo1. These studies provide important cellular and molecular insights into understanding how SSA-induced regeneration of the hematopoietic compartment can underpin recovery of the immune system following cell-damaging cancer therapies. These findings support a short-term strategy for clinical use of SSA to enhance the production of lymphoid cells and HSC engraftment, leading to improved outcomes in adult patients undergoing HSCT and immune depletion in general.


Age-related deterioration in blood vessels and the broader cardiovascular system generates damage in the brain. Blood vessel walls are elastic, a property that depends on the molecular structure of the proteins making up the extracellular matrix in that tissue. This structure is progressively degraded by the presence of sugary metabolic waste known as advanced glycation end-products (AGEs), which leads to the formation of cross-links between proteins and a consequent loss of elasticity. Stiffening of blood vessels causes hypertension and many of the cellular and molecular mechanisms involved overlap with those that speed the progression of atherosclerosis, a condition in which blood vessel walls become sources of chronic inflammation and are remodeled into fatty deposits by abnormal cellular activity. All of this causes a rising number of structural failures in the small blood vessels of the brain. Each one is effectively a tiny, unnoticed stroke, killing cells in a minuscule area of the brain. This harm adds up over time and is one of the contributing causes of age-related cognitive impairment.

A recently published paper suggests that more of the age-related changes observed in the brain may be due to vascular degeneration than previously thought. If so this implies that research aimed at removing cross-links has a greater importance, as do efforts to block the very early causes of atherosclerosis, such as the generation of oxidized lipids due to mitochondrial DNA damage. It also places a greater value on the basics of cardiovascular health in general: fitness, exercise, resilience, and so forth. When it comes to longevity and medicine, we must protect the brain: all other parts of the body could, in theory, be completely rebuilt or replaced if that becomes necessary, but the structure of the brain is the structure of the self. Lose that and there is nothing that can be done. Retain it and even if you must be cryopreserved as a last resort, there is still a chance at a future.

Human brains age less than previously thought

Older brains may be more similar to younger brains than previously thought. Researchers have demonstrated that previously reported changes in the ageing brain using functional magnetic resonance imaging (fMRI) may be due to vascular (or blood vessels) changes, rather than changes in neuronal activity itself. Given the large number of fMRI studies used to assess the ageing brain, this has important consequences for understanding how the brain changes with age and challenges current theories of ageing. A fundamental problem of fMRI is that it measures neural activity indirectly through changes in regional blood flow. Thus, without careful correction for age differences in vasculature reactivity, differences in fMRI signals can be erroneously regarded as neuronal differences. An important line of research focuses on controlling for noise in fMRI signals using additional baseline measures of vascular function. However, such methods have not been widely used, possibly because they are impractical to implement in studies of ageing.

An alternative candidate for correction makes use of resting state fMRI measurements, which is easy to acquire in most fMRI experiments. While this method has been difficult to validate in the past, the unique combination of an impressive data set across 335 healthy volunteers over the lifespan, as part of the CamCAN project, allowed researchers to probe the true nature of ageing effects on resting state fMRI signal amplitude. Their research showed that age differences in signal amplitude during a task are of a vascular, not neuronal, origin.

The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults

In functional magnetic resonance imaging (fMRI) research one is typically interested in neural activity. However, the blood-oxygenation level-dependent (BOLD) signal is a composite of both neural and vascular activity. As factors such as age or medication may alter vascular function, it is essential to account for changes in neurovascular coupling when investigating neurocognitive functioning with fMRI. The resting-state fluctuation amplitude (RSFA) in the fMRI signal has been proposed as an index of vascular reactivity.

The use of RSFA is predicated on its sensitivity to vascular rather than neural factors. The effects of ageing on RSFA were significantly mediated by vascular factors, but importantly not by the variability in neuronal activity. The scaling analysis revealed that much of the effects of age on task-based activation studies with fMRI do not survive correction for changes in vascular reactivity, and are likely to have been overestimated in previous fMRI studies of ageing.


Everything we know about the way in which people fall apart with age is based on what happened in the past. The research community has access to centuries of good epidemiological data to demonstrate what to expect in old age both with and without modern medicine. Though when you stop to think about the old today, bear in mind that the oldest old spent most of their old age in a time prior to genetic testing, highly effective heart therapies, and many other developments of the past twenty years. Those who are merely elderly still lived half their lives in a medical environment that would appear extremely primitive to anyone forced to cope with it today. We don't tend to think of the period from the 1940s to the 1960s as a backwards era of low-tech medicine, as little separates us culturally from those years, but the widely available medicine of the time was indeed lacking in comparison to today's technology.

Life expectancy is an odd and often misunderstood measure. It doesn't predict future life spans, but rather is a statistical measure of the average life span of a given birth year cohort if they relived the same life history as did the present population of old people. That means the same technologies, the same economic circumstances, the same pace of progress, and so forth. Obviously that won't happen: life expectancy is a useful statistical measure for comparing progress in medicine from year to year, and it does keep on going up, but it isn't a useful tool to inform you of how long you will live. That timeline remains to be determined, and we live in a time of very rapid improvement in biotechnology.

At the best of times there is a decade of lag between laboratory demonstrations and widespread availability in the clinic, and the present state of regulation is far from the best of times. There is a growing disconnect between the accelerating progress of cellular biotechnology and the ever heavier ball and chain shackled to clinical implementation of that research. The gap is widening now, but I think that in the future medical tourism and competition between regulatory regions will overcome this issue: there will be a sudden flood of pent up technology over a fairly short period of time, but who knows when the dam will finally break. The costs of medical development are falling to ever smaller fractions of the present cost of regulatory compliance: if development to the point of practical and reasonably safe usability costs $50 million while compliance costs $500 million, and that isn't too far from the actual state of affairs, then something has to give.

The modern upward trend in adult life expectancy has spanned centuries, created first by control over sanitation and infectious disease, and later by increasingly effective treatments for age-related conditions. We should not expect this to continue as it has been, however. This decade and the opening years of the next are an important transitional period, a shift between (a) the past age in which no attempt was made to treat the causes of aging as a medical condition and (b) the new era in which researchers are focused on aging itself rather than merely patching over its consequences. We should expect a great difference in the trendline of human longevity in the decades ahead precisely because there is a great difference between trying to treat aging and not trying to treat aging.

Thus this paper is not a roadmap for the future of those in their 30s and 40s today. Rather it is a look back at the results of the past for those who are old today:

Age-Related Variation in Health Status after Age 60

Disability, functionality, and morbidity are often used to describe the health of the elderly. Although particularly important when planning health and social services, knowledge about their distribution and aggregation at different ages is limited. The older population consists of an extremely heterogeneous group of persons; the older the age group, the greater the variation found in cognition, physical and sensory function, and social engagement, to mention just a few examples.

We aim to characterize the variation of health status in 3080 adults 60+ living in Sweden between 2001 and 2004 and participating at the SNAC-K population-based cohort study using five indicators of health separately and in combination: number of chronic diseases, gait speed, Mini Mental State Examination (MMSE), disability in instrumental-activities of daily living (I-ADL), and in personal-ADL (P-ADL). Probability of multimorbidity and probability of slow gait speed were already above 60% and 20% among sexagenarians. Median MMSE and median I-ADL showed good performance range until age 84; median P-ADL was close to zero up to age 90. 30% of sexagenarians and 11% of septuagenarians had no morbidity and no impairment, 92% and 80% of them had no disability. 28% of octogenarians had multimorbidity but only 27% had some I-ADL disability. Among nonagenarians, 13% had severe disability and impaired functioning while 12% had multimorbidity and slow gait speed.

In this large cohort, we were able to capture the complexity and heterogeneity of health status in 60+ old adults. Until 80, most people do not have functional impairment or disability, despite the presence of morbidity or even multimorbidity. Disability is common only after age 90. The 80s are a transitional period when major health changes take place; often following the co-occurrence of more than one negative health event. If we consider good health as the absence of chronic diseases, functional impairment, and disability, good health is still the most prevalent pattern among sexagenarians. However, even among octogenarians, the most prevalent health state is characterized by presence of chronic disorders with impairment only in gait speed. In other words, morbidity and multimorbidity start early in late adulthood, but functional dependence becomes common only for people older than age 90.


Monday, March 2, 2015

Regular readers know that significant progress towards human rejuvenation, ending frailty and disease in aging, requires that SENS research, or something very like it, disrupts the present status quo to become the scientific mainstream in this field. SENS is focused on periodic repair of the fundamental damage to cells and macromolecules that occurs as a side-effect of the ordinary operation of metabolism. A strong focus here is on the accumulation of metabolic byproducts such as amyloids, lipofuscin and cross-links, while in comparison age-related changes in telomere biochemistry and epigenetic patterns are not all that important as targets: changes there are secondary effects, and thus should be reversed if the underlying damage is repaired.

In comparison the mainstream high level research strategy for aging and longevity is the other way around for these areas; there is comparatively little concern with metabolic byproducts as a target for treatment outside of the Alzheimer's field, and a great deal of interest in targeting telomeres and epigenetic changes. In general this is driven by a philosophy of metabolic alteration: the guiding principles are to (a) find ways to change the operation of metabolism to slow down the accumulation of damage and thus slow aging, or (b) force metabolic control processes back into a youthful configuration. This is a far worse approach than damage repair; it cannot produce rejuvenation, and in many cases ignores the root causes of aging while trying to force damaged biochemistry to behave as though it were not damaged and aged. We should expect only marginal outcomes from such efforts.

Both SENS and the present mainstream overlap in their concern for cancer and stem cell function. Both consider mitochondrial function important in aging, but with important differences in the present consensus of how and why it is important, and what should be done as a result. In the SENS vision, stochastic nuclear DNA damage is probably not all that important outside of cancer, but the mainstream consensus is that it probably is a cause of age-related disregulation of cellular activities and tissue function. This article reflects the mainstream view:

Age is the number one risk factor for myriad diseases, including Alzheimer's, cancer, cataracts, and macular degeneration. And while researchers are making progress in understanding and treating each of these ailments, huge gaps remain in our understanding of the aging process itself. The aging process can be traced down to the level of cells, which themselves die or enter senescence as they age, and even to the genomic level. Accumulation of mutations and impairments in DNA repair processes are highly associated with symptoms of aging. In fact, disorders that cause premature aging are typically caused by mutations in genes involved in the maintenance of our DNA. And at the cellular level, decreases in stem cells' proliferative abilities, impairments in mitochondrial function, and proneness to protein misfolding can all contribute to aging. As scientists continue to detail these various processes, the big question is, "At what step along all these pathways is the best place to intervene to try to promote healthy aging? The therapeutic goal would be to increase health span, not life span. There's nothing fun about living to be really old if your health diminishes to the point that it's no longer fun to be alive."

As DNA replicates, the cellular machinery involved in the process makes mistakes, leading to changes in the DNA sequence. While it's unclear exactly how DNA damage contributes to aging, what's certain is that the damage and mutations contribute to cancer, "There is this exponential increase in cancer risk during aging, so it's not at all unlikely . . . that accumulation of damage to the genome is really a major factor here." Premature-aging diseases in humans also point to the role of DNA repair and stabilization mechanisms in the aging process. But how DNA damage leads to aging in normal adults remains an open question.

Epigenetic marks shift over time in a variety of healthy cells. Indeed, mapping of DNA methylation in human cells has shown that some areas of the genome become hypermethylated with age, while others show reduced methylation. Histone modifications, another type of epigenetic mark, have also been shown to change with age in some human tissues. The question now is whether these epigenetic changes influence aging. "Is this an epiphenomenon that happens just because we age, or is it actually causing symptoms or diseases of aging and limiting life span?"

A particularly influential form of DNA damage occurs at telomeres, the repetitive sequences that cap chromosomes and shorten with age. While germ and stem cells express an enzyme called telomerase that replenishes telomeres, most cells' telomeres shrink with every division, due to the fact that DNA polymerase cannot fully replicate the ends of chromosomes. If the telomeres shrink too much or are damaged, cells undergo apoptosis or enter senescence. Telomere damage has clear effects on aging. Mice with short telomeres have diminished life spans and reduced stem-cell and organ function, while mice whose telomerase is enhanced in adulthood age more slowly.

Life depends on proper protein function. And proper protein function is all about proper protein folding. Misshapen proteins are often rendered useless and can clump together with other misfolded proteins inside cells. It is not yet clear whether protein misfolding leads to aging, but it appears that it is an almost inevitable physiological reality that the two coincide. To add insult to injury, advancing age also brings about the decline of molecular chaperones that aid in the folding process and of protective pathways that normally help clear misfolded proteins from cells. "The big open question is whether the accumulation of misfolded protein aggregates is the cause or consequence of the aging process. The hypothesis is that maybe there is a widespread accumulation of misfolded protein aggregates affecting all cells in the body, and that produces progressive dysfunction of cells in the body that leads to aging."

There is a new view of oxidative damage to mitochondria. "If damage is not too severe, there's some sort of protective response. What won't kill you makes you stronger." There is a limit to how much damage the organelle can handle, however, and mitochondrial dysfunction may well contribute to aging. "It's consistent with this idea that maybe from metabolism you get oxidative stress, you then get DNA damage, then that decline in mitochondrial function makes us age." Mitochondria's role in aging is likely not limited to oxidative or even DNA damage. Given the organelles' broad-reaching involvement in metabolism, inflammation, and epigenetic regulation of nuclear DNA. "They may be central integrators of many of the pathways we've implicated in aging."

Healthy adults produce about 200 billion new red blood cells each day to replace the same number removed from circulation every 24 hours. But the rate of blood-cell production declines with age. "It's a bit of a mystery as to why these self-renewing cells in different tissues stop working. The nature of molecular aging at the cellular level is not fully known." Researchers have also linked epigenetic alterations, such as locus-specific changes in DNA methylation, to the reduced regenerative capacity of stem cells with age. And age-related shifts in the environment in which stem cells divide and differentiate, dubbed the stem-cell niche, may also contribute to stem-cell aging. Exactly why and how stem cells slow down with age is still a mystery.

Stem cells and other cells that undergo damage and decline do not age in isolation. Researchers are finding that some processes of aging influence the release of regulators that circulate in the blood. "At one time, everybody thought, well, cells just get old and die. But the cells do more than just die. They do negative things, and they persist." One such regulator is growth differentiation factor 11 (GDF11), which measurably decreases with age. Researchers found that young blood can restore some lost functions in the hearts, brains, and skeletal muscles of older mice, and that these effects can be replicated by treating old mice with GDF11. The researchers are now working to pinpoint the sources of circulating GDF11, as well as to understand the mechanisms by which it remodels aging tissues.

Many of the questions voiced in the article could be answered most cost-effectively by implementing the SENS research programs to the point of demonstrating all of the repair biotechnologies in mice, and then observing the results. At this time it is estimated that the cost of doing so is about a decade of time and perhaps a billion dollars; this is about the same cost as is incurred in the development of a single new drug. It seems well worth doing.

Monday, March 2, 2015

The liver is the most regenerative of organs in mammals, capable of regrowing much of its mass. That is arguably less important than the ability of a complete liver to regenerate the damage of aging and disease, such as growing fibrosis and dysfunction in cell populations necessary for organ function. Deployment of therapies to reliably achieve this goal still lies ahead, but researchers are making slow progress in the right direction:

The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation mainly by deactivating anti-oncogenes. However, in this work, we identified an unexpected role of Wip1 in liver regeneration. In contrast to its known role in promoting cell proliferation in extra-hepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PH). Deletion of Wip1 increased the rate of liver regeneration following partial hepatectomy.

The enhanced liver regeneration in Wip1 deficient mice was due to the activation of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mammalian target of rapamycin (mTOR). Interestingly, inhibition of Wip1 also activated p53 pathway during liver regeneration. Disruption of the p53 pathway further enhanced the liver regeneration in Wip1 deficient mice. Therefore, inhibition of Wip1 has a dual role in liver regeneration, i.e. promoting hepatocyte proliferation via activation of mTORC1 pathway, meanwhile suppressing liver regeneration through activation of p53 pathway.

For the first time we demonstrate that mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. Therefore, our findings have clinical applications in cases where liver regeneration is critical, including acute liver failure, cirrhosis or small-for-size liver transplantations.

Tuesday, March 3, 2015

This article goes into some detail on recent research into whether retrotransposons in the genome play a meaningful role in aging. This is analogous to the debate over whether stochastic nuclear DNA damage has a role in aging beyond causing cancer, and the sort of studies you'd need to introduce clear proof one way or another are much the same:

Retrotransposons, often referred to as jumping genes, are mobile genetic elements that parasitize host machinery to replicate themselves across the genome. Since their emergence more than 100 million years ago, retrotransposons have been enormously successful. Modern mammalian genomes, for example, are riddled with the scars of these copy-and-paste events, with retrotransposon-derived DNA now accounting for nearly 50 percent of the human genome.

The most dangerous retrotransposon in mammalian genomes is the long interspersed nuclear element-1 (LINE-1 or L1). L1 retrotransposons are a little more than 6 kilobases long and encode an RNA-binding protein and an endonuclease with reverse-transcriptase activity that allow the element to autonomously replicate in the host genome via an RNA intermediate. The human genome contains more than 500,000 copies of L1s. Although the vast majority of these have been inactivated as a result of truncation, mutation, and internal rearrangement, it is estimated that approximately 100 of these L1s per nuclear genome still retain their replication activity. Despite their abundance, however, L1s are not benign. Rather, their activity, and even their presence, represents a real danger to the host, increasing the risk of DNA damage, cancer, and other maladies. Given the consequences of L1 activity, it is unsurprising that host genomes devote considerable resources to suppressing these retrotransposons. Indeed, every step of the L1 life cycle is impeded in some way by host factors such as gene silencing, antiviral defense machinery, small RNAs, and autophagy.

Historically, little attention has been given to retrotransposition in somatic tissue, because this was thought of as an evolutionary dead end. In recent years, however, evidence has accumulated that L1 elements can become active in a variety of somatic tissues in humans and mice, including in the brain, skeletal muscle, heart, and liver. Intriguingly, some of the highest L1 activity has been observed in aging tissues, particularly those affected by age-related pathologies such as cancer. This raises the interesting possibility that L1 activity may contribute to the aging process. Increased DNA damage and mutagenesis are prevalent in aging tissues, and L1 activity is known to increase following such damage. In addition, a small number of studies have shown that overexpression of L1 can cause cells to senesce, a hallmark of aging tissues. The role of L1 in driving age-related processes is now a topic ripe for study.

Tuesday, March 3, 2015

Nitric oxide is present in many areas of metabolism that change with aging or that influence the pace of aging. Calorie restriction results in increased nitric oxide levels, for example, though as always researchers are far from putting all the pieces of the calorie restriction response together in a neat arrangement of cause and effect. Nitric oxide levels are thought to influence mitochondrial activity and stem cell populations as well, and both of those are important in aging. There is interest in trying to manipulate nitric oxide mechanisms in efforts to slow the progression of aging:

Nutrition and medical advancements leading to increased lifespan are not adequately translating into improved healthspan. Present-day gerontology research suggests that, unlike traditional approaches that focus on specific diseases, deciphering, and targeting the aging process itself could be the most clever approach toward increased healthspan.

Multiple cell effectors work together to cause the senescent cell phenotype. Particularly, two cellular organelles - nucleus and mitochondrion - have been implicated in the "wear and tear" aspects of aging. Nitric oxide (NO) generated through the endothelial nitric oxide synthase (eNOS) acts to promote mitochondrial biogenesis and bioenergetics, with a favorable impact in diverse chronic diseases of the elderly. Obesity, diabetes and aging share common pathophysiological mechanisms, including mitochondrial impairment and dysfunctional eNOS. Here we review the evidences that eNOS-dependent mitochondrial biogenesis and quality control, and possibly the complex interplay among cellular organelles, may be affected by metabolic diseases and the aging processes, contributing to reduce healthspan and lifespan.

Though still in its infancy, research on the role of the eNOS-NO system in the control of cell organelle connections and quality control might reveal exciting avenues for disease treatment in the coming years. The development of novel therapies aiming to preserve eNOS-NO signaling will benefit from the identification of site-specific interaction with the eNOS structure. Drugs or nutrients able to sustain the eNOS-NO generating system might contribute to maintain organelle homeostasis and represent novel preventive and/or therapeutic approaches to chronic age-related diseases. Efforts to identify druggable eNOS sites are ongoing, although our knowledge about the therapeutic usability of the proposed eNOS-targeting molecules in the long-term is limited.

Wednesday, March 4, 2015

Regular moderate exercise is correlated with greater life expectancy in humans and shown to cause greater life expectancy in animal studies. It definitely improves health. Thus now that more of the mechanisms of exercise are understood, researchers are interested in uncovering molecular targets and drugs that can reproduce some of those effects:

Scientists have discovered a new hormone that fights the weight gain caused by a high-fat Western diet and normalizes the metabolism - effects commonly associated with exercising. Hormones are molecules that act as the body's signals, triggering various physiological responses. The newly discovered hormone, dubbed "MOTS-c," primarily targets muscle tissue, where it restores insulin sensitivity, counteracting diet-induced and age-dependent insulin resistance.

To test the effects of MOTS-c, the team injected the hormone into mice fed a high-fat diet, which typically causes them to grow obese and develop a resistance to insulin. The injections not only suppressed both effects in mice, they also reversed age-dependent insulin-resistance, a condition that precedes diabetes. "This discovery sheds new light on mitochondria and positions them as active regulators of metabolism." MOTS-c is unique among hormones in that it is encoded in the DNA of mitochondria - the "powerhouses" of cells that convert food into energy. Other hormones are encoded in DNA in the nucleus.

While all of the experiments on MOTS-c to date have been performed on lab mice, the molecular mechanisms that make it function in mice exist in all mammals, including humans. The MOTS-c intellectual property has been licensed to a biotechnology company, and clinical trials in humans could begin within the next three years.

Wednesday, March 4, 2015

The quality of cartilage tissue depends upon its mechanical properties. In past years getting that right has proven to be challenging: growing cartilage cells is one thing, but forming the correct three-dimensional structures and extracellular matrix so that the resulting tissue can bear load is quite another. Nonetheless, progress has been made. To follow on from a recent demonstration of cartilage regeneration using induced pluripotent stem cells, here another group is using embryonic stem cells to regrow cartilage in situ:

Researchers have developed a protocol under strict laboratory conditions to grow and transform embryonic stem cells into cartilage cells (also known as chondrocytes). "This work represents an important step forward in treating cartilage damage by using embryonic stem cells to form new tissue, although it's still in its early experimental stages." During the study, the team analysed the ability of embryonic stems cells to become precursor cartilage cells. They were then implanted into cartilage defects in the knee joints of rats. After four weeks cartilage was partially repaired and following 12 weeks a smooth surface, which appeared similar to normal cartilage, was observed. Further study of this newly regenerated cartilage showed that cartilage cells from embryonic stem cells were still present and active within the tissue.

Developing and testing this protocol in rats is the first step in generating the information needed to run a study in people with arthritis. Before this will be possible more data will need to be collected to check that this protocol is effective and that there are no toxic side-effects. But researchers say that this study is very promising as not only did this protocol generate new, healthy-looking cartilage but also importantly there were no signs of any side-effects such as growing abnormal or disorganised, joint tissue or tumours. Further work will build on this finding and demonstrate that this could be a safe and effective treatment for people with joint damage.

Thursday, March 5, 2015

Researchers have put some numbers to the life expectancy lost to obesity and its most common associated conditions. The message, as always, is that it is a bad idea to let yourself accumulate excess fat tissue. It is easy to let things slide in that direction in this modern age of comparative wealth and plenty, but there are consequences, even for being just moderately overweight:

Obesity, hypertension and diabetes are known risk factors for heart failure, a chronic condition in which the heart cannot pump enough blood to meet the body's needs. For the first time, scientists have quantified the average number of heart failure-free years a person gains by not developing those risk factors by age 45. The study found that people who had obesity, hypertension and diabetes by age 45 were diagnosed with heart failure 11 to 13 years earlier, on average, than people who had none of those risk factors by age 45. People who had only one or two of the risk factors, but not all three, developed heart failure an average of three to 11 years earlier than people with none of the risk factors. Despite advances in heart disease treatment and prevention, the pattern was consistent across data collected over the past 40 years. "The associations between these risk factors and heart failure has been remarkably stable over time. Although the prevalence of some of these risk factors has changed, the association remains the same."

"The message from this study is that you really want to prevent or delay the onset of these risk factors for as long as possible. Doing so can significantly increase the number of years you are likely to live free of heart failure. In the clinic, we often give patients metrics of risk that are relative and abstract. It's a much more powerful message, when you're talking to patients in their 30s or 40s, to say that they will be able to live 11 to 13 years longer without heart failure if they can avoid developing these three risk factors now."

Thursday, March 5, 2015

Many people believe that medical control over aging will be stunningly expensive, and thus indefinite extension of healthy life will only be available to a wealthy elite. This is far from the case. If you look at the SENS approach to repair therapies, treatments when realized will be mass-produced infusions of cells, proteins, and drugs. Everyone will get the same treatments because everyone ages due to the same underlying cellular and molecular damage. You'll need one round of treatments every ten to twenty years, and they will be given by a bored clinical assistant. No great attention will be needed by highly trained and expensive medical staff, as all of the complexity will be baked into the manufacturing process. Today's closest analogs are the comparatively new mass-produced biologics used to treat autoimmune conditions, and even in the wildly dysfunctional US medical system these cost less than ten thousand dollars for a treatment.

Rejuvenation won't cost millions, or even hundreds of thousands. It will likely cost less than many people spend on overpriced coffee over the course of two decades of life, and should fall far below that level. When the entire population is the marketplace for competing developers, costs will eventually plummet to those seen for decades-old generic drugs and similar items produced in factory settings: just a handful of dollars per dose. The poorest half of the world will gain access at that point, just as today they have access to drugs that were far beyond their reach when initially developed.

Nonetheless, many people believe that longevity enhancing therapies will only be available for the wealthy, and that this will be an important dynamic in the future. Inequality is something of a cultural fixation at the moment, and it is manufactured as a fantasy where it doesn't exist in reality. This is just another facet of the truth that most people don't really understand economics, either in the sense of predicting likely future changes, or in the sense of what is actually taking place in the world today:

The attitude now towards disease and old age and death is that they are basically technical problems. It is a huge revolution in human thinking. Throughout history, old age and death were always treated as metaphysical problems, as something that the gods decreed, as something fundamental to what defines humans, what defines the human condition and reality. Even a few years ago, very few doctors or scientists would seriously say that they are trying to overcome old age and death. They would say no, I am trying to overcome this particular disease, whether it's tuberculosis or cancer or Alzheimers. Defeating disease and death, this is nonsense, this is science fiction.

But, the new attitude is to treat old age and death as technical problems, no different in essence than any other disease. It's like cancer, it's like Alzheimers, it's like tuberculosis. Maybe we still don't know all the mechanisms and all the remedies, but in principle, people always die due to technical reasons, not metaphysical reasons. In the middle ages, you had an image of how does a person die? Suddenly, the Angel of Death appears, and touches you on the shoulder and says, "Come. Your time has come." And you say, "No, no, no. Give me some more time." And Death said, "No, you have to come." And that's it, that is how you die.

We don't think like that today. People never die because the Angel of Death comes, they die because their heart stops pumping, or because an artery is clogged, or because cancerous cells are spreading in the liver or somewhere. These are all technical problems, and in essence, they should have some technical solution. And this way of thinking is now becoming very dominant in scientific circles, and also among the ultra-rich who have come to understand that, wait a minute, something is happening here. For the first time in history, if I'm rich enough, maybe I don't have to die.

Death is optional. And if you think about it from the viewpoint of the poor, it looks terrible, because throughout history, death was the great equalizer. The big consolation of the poor throughout history was that okay, these rich people, they have it good, but they're going to die just like me. But think about the world, say, in 50 years, 100 years, where the poor people continue to die, but the rich people, in addition to all the other things they get, also get an exemption from death. That's going to bring a lot of anger.

And again, I don't want to give a prediction, 20 years, 50 years, 100 years, but what you do see is it's a bit like the boy who cried wolf, that, yes, you cry wolf once, twice, three times, and maybe people say yes, 50 years ago, they already predicted that computers will replace humans, and it didn't happen. But the thing is that with every generation, it is becoming closer, and predictions such as these fuel the process.

The same thing will happen with these promises to overcome death. My guess, which is only a guess, is that the people who live today, and who count on the ability to live forever, or to overcome death in 50 years, 60 years, are going to be hugely disappointed. It's one thing to accept that I'm going to die. It's another thing to think that you can cheat death and then die eventually. It's much harder. While they are in for a very big disappointment, in their efforts to defeat death, they will achieve great things. They will make it easier for the next generation to do it, and somewhere along the line, it will turn from science fiction to science, and the wolf will come.

Friday, March 6, 2015

Epidemiological studies of members of long-lived families are driving much of the interest in the genetics of longevity. While it is thought that genetic variations are much less important than lifestyle choices, they appear to become more influential in extreme old age, in the period of life when individuals are very damaged and frail. Investigating the root causes of such variations in human longevity is good science, but probably irrelevant to the future of longevity-enhancing medicine: effective therapies will repair damage and keep people young, indefinitely postponing the phase of life and loss of function in which genetic differences have any meaningful effect.

In this study, members of long-lived families are compared with age-matched individuals from families of ordinary longevity, and they are largely more healthy, as you'd expect. Aging is a global phenomenon of damage accumulation, and people who live longer tend to be less damaged and thus more healthy at a given age. Other studies have provided evidence for a genetic component to familial longevity, but note the spouse effect here however. That spouses marrying into long-lived families are also more healthy than the general population suggests that lifestyle choices continue to have a fairly strong influence on this data even in later ages:

The Long Life Family Study (LLFS) is a multicenter longitudinal study of exceptional survival among members of long-lived sibships (probands), their offspring, and spouses of either group. For these four "roles", we asked: Does membership in a long-lived family protect against disease? We used 2008-2010 Beneficiary Annual Summary Files from the Centers for Medicare & Medicaid Services (CMS) to compare prevalences of 17 conditions among 781 LLFS participants in Medicare with those of 3,227 non-LLFS matches from the general Medicare population.

Seven conditions were significantly less common among LLFS probands than their matches: Alzheimer's, hip fracture, diabetes, depression, prostate cancer, heart failure, and chronic kidney disease. Four diseases not strongly linked to mortality (arthritis, cataract, osteoporosis, glaucoma) were significantly more common for LLFS probands. Despite fewer people and less disease in those roles, LLFS offspring and LLFS spouses of either generation also had significantly lower risk for Alzheimer's, diabetes, and heart failure.

Common, severe mortality-associated diseases are less prevalent among LLFS probands and their offspring than in the general population of aging Americans. Quality-of-life-limiting diseases such as arthritis and cataract are more prevalent, potentially through more diagnosing of milder forms in otherwise healthy and active individuals. LLFS spouses are also relatively healthy. As the younger cohorts age into Medicare and develop more conditions, it will be important to see whether these tentative findings strengthen.

Friday, March 6, 2015

One interesting correlation that has emerged fairly recently from very large epidemiological studies of health is that sitting time is associated with worse health and a shorter life expectancy independently of exercise. Explaining why this is the case is a still a fairly speculative process at this stage, but a first step is to try to pin down specific aspects of age-related disease and degeneration and associate those with sitting time.

Here researchers focus on the calcification of blood vessels, a part of the mineralization of connective tissues that occurs in aging. Along with cross-linking due to sugary metabolic waste, this process stiffens blood vessel walls. This in turn causes hypertension, contributes to atherosclerosis, and causes all sorts of further damage to tissues throughout the body due to structural failure in small blood vessels and inappropriate blood pressure. As for cross-links, there is a minimal amount of research taking place on how to demineralize tissues, but far from enough.

Sitting for many hours per day is associated with increased coronary artery calcification, a marker of subclinical heart disease that can increase the risk of a heart attack. The study found no association between coronary artery calcification and the amount of exercise a person gets, suggesting that too much sitting might have a greater impact than exercise on this particular measure of heart health. The results suggest that exercise may not entirely counteract the negative effects of a mostly sedentary lifestyle on coronary artery calcium. "It's clear that exercise is important to reduce your cardiovascular risk and improve your fitness level. But this study suggests that reducing how much you sit every day may represent a more novel, companion strategy (in addition to exercise) to help reduce your cardiovascular risk."

Coronary artery calcification, measured through a non-invasive CT heart scan, indicates the amount of calcium contained in plaques within the heart's arteries. Coronary artery disease occurs when such plaques accumulate over time, causing the arteries to narrow. Analyzing heart scans and physical activity records of more than 2,000 adults living in Dallas, the researchers found each hour of sedentary time per day on average was associated with a 14 percent increase in coronary artery calcification burden. The association was independent of exercise activity and other traditional heart disease risk factors. A particular strength of the study is that the researchers used a motion-tracking device called an accelerometer to measure how long participants were sedentary and how much they exercised, whereas most previous studies have relied on surveys.


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