Fight Aging! Newsletter, June 1st 2015

June 1st 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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  • A Few New Fight Aging! Fundraising Posters
  • A Collection of Recent Mitochondrial Research
  • Why Seek to Classify Aging as a Disease?
  • Diving Deeper into the Biochemistry of Muscle Aging
  • Why Does Human Post-Reproductive Longevity Exist?
  • Latest Headlines from Fight Aging!
    • Linking Mitochondrial DNA Damage and Glaucoma
    • Neural Stem Cell Transplant Treats Parkinson's in Rats
    • Brain Preservation Foundation Prize Update
    • Male Offspring in Long-Lived Families are Less Fat
    • Another Example of Induced Pluripotency Reversing Mitochondrial Damage in Aging
    • Horizons: Extending Lives, Defying Mortality
    • Cellular Senescence and Stem Cell Aging
    • Inching Towards Treatments that Manipulate Heat Shock Protein Activity
    • Gender Differences in Methods of Slowing Aging
    • A Null Result for Vigorous Exercise and Telomere Length


We are nearing the first phase of this year's Fight Aging! fundraiser in support of the rejuvenation research programs carried out at the SENS Research Foundation. We are on the cusp of important progress in medical science, balanced close to a shift from the less effective research strategies of the past to SENS-like repair biotechnologies of the future. The frailty and disease that presently accompanies aging will be defeated by addressing its root causes, through means that are already clearly envisaged: it is only hard work and funding that separates the state of medicine today from a near future in which aging is brought under medical control. The road ahead for research and development is just about as clear and direct as these things ever get. I'll be asking people to step forward and contribute, just as last year, but there are a few things left to organize first. Don't let that stop you from sending me email if you have the ability to help.

Among the items left to be done before the later stages of the fundraiser roll around is the creation of a new brace of fundraising posters. I'd like to put together something more general and diverse this year, at least in comparison to last year's two posters. Primary colors, large text, flat backgrounds; the sort of thing that makes it easier for other advocates to retool the wording for their own usage. Not coincidentally, it also makes it easier for me to try out a more ideas prior to pulling in a professional. If some of them turn out to be terrible ideas, well, no great loss. There are always the others. Not all of us are Photoshop wizards, but simple poster designs go a long way towards letting everyone play.

This latest attempt is intended for placards and other printed displays, where the color catches the eye but is nowhere near as lurid as it appears upon your screen just about now. For those who want to tinker, the font used here is Tex Gyre Heros bold condensed, at 500px and 200px for the two sizes:

Choose Life: Scientists Work to End Frailty Poster: 4200 x 2800px

Choose Life: No More Frailty Poster: 4200 x 2800px


Mitochondria are the power plants of the cell, a herd of cell components evolved from symbiotic bacteria that are responsible for generating energy supplies to power cellular processes, among other tasks. Mitochondria are important in aging, and their dysfunction is involved in many age-related conditions; that much is the consensus in the scientific community. After that, however, there is much ongoing debate and a rapid generation of new papers when it comes to the details of what exactly it is that matters, which aspect of age-related mitochondrial changes are most important, and what the various chains of cause and consequence look like.

There are numerous different research perspectives to muddy the waters, of course. Not every wise man is looking at the same part of the elephant. For example, scientists primarily interested in slowing aging via some form of drug-based therapy tend to look at mitochondria and aging through the lens of cellular housekeeping and mitohormesis. In some genetic or other interventions shown to extend healthy life spans in laboratory species, mitochondria emit more reactive molecules in the course of supplying the cell with stored chemical energy, which causes cells to react with greater housekeeping efforts - and the result is a net gain in reduction of damage. There are other perspectives, however, leading on from variants of the mitochondrial free radical theory of aging in which mitochondrial DNA damage is seen as the start of a chain of consequences that leads to malfunctioning cells. Mitochondria need the right protein building blocks in order to function, and if the genes encoding those proteins are broken, then failures begin to occur. Some of the SENS rejuvenation research programs follow on from that theory, and so attempt to ensure that even with DNA damage, the proteins will be available. There are other potential approaches to repair and workaround as well.

These are not the only viewpoints. Many researchers have very narrow interests in mitochondrial function with respect to one specific age-related condition, and are focused down on that one thin slice of biochemical complexity. Then there are those scientists who work to catalog natural variations in longevity and their genetic causes, engaged in identifying a contribution caused by different mitochondrial haplogroups through surveys of population data. Were scientists more minded towards intervention this could be the starting point on the road to developing a better set of mitochondrial DNA, an improved, optimized version that could be provided via gene therapy. Not as important as learning how to fix the set of mitochondrial DNA we have, of course: it doesn't much matter that your engine is more fuel-efficient if you still cannot repair it.

But you get the picture. Mitochondria research is a very active field, with a lot of different goals, interests, and back and forth at the cutting edge. New data arrives on a weekly basis, and always something in there to disagree with. Here is a small collection of some recent papers, which should give you an insight into how things go in this slice of aging research.

Reconsidering the Role of Mitochondria in Aging

Mitochondrial dysfunction has long been considered a major contributor to aging and age-related diseases.The Mitochondrial Free Radical Theory of Aging postulated that somatic mitochondrial DNA mutations that accumulate over the life span cause excessive production of reactive oxygen species that damage macromolecules and impair cell and tissue function. Indeed, studies have shown that maximal oxidative capacity declines with age while reactive oxygen species production increases. The hypothesis has been seriously challenged by recent studies showing that reactive oxygen species evoke metabolic health and longevity, perhaps through hormetic mechanisms that include autophagy.

The importance of mitochondrial biology as a trait d'union between the basic biology of aging and the pathogenesis of age-related diseases is stronger than ever, although the emphasis has moved from reactive oxygen species production to other aspects of mitochondrial physiology, including mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics. Mitochondria could play a key role in the pathophysiology of aging or in the earlier stages of some events that lead to the aging phenotype. Therefore, mitochondria will increasingly be targeted to prevent and treat chronic diseases and to promote healthy aging.

Mechanisms linking Mitochondrial DNA damage and aging

In the last century, considerable efforts were made to understand the role of mitochondrial DNA (mtDNA) mutations and of oxidative stress in aging. The classic mitochondrial free radical theory of aging, in which mtDNA mutations cause genotoxic oxidative stress, which in turn creates more mutations, has been a central hypothesis in the field for decades. In the last few years, however, new elements have discredited this original theory. The major source of mitochondrial DNA mutations seems to come from replication errors and failure of the repair mechanisms, and the accumulation of these mutations as observed in aged organisms appears to occur by clonal expansion and are not caused by a reactive oxygen species-dependent vicious cycle.

New hypotheses of how age-associated mitochondrial dysfunction may lead to aging are based on the role of reactive oxygen species as signaling molecules and on their role in mediating stress responses to age-dependent damage. Here, we review the changes that mtDNA undergoes during aging, and the past and most recent hypotheses linking these changes to the tissue failure observed in aging.

Dietary restriction, mitochondrial function and aging: from yeast to humans

Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on healthspan and lifespan.

A Mitochondrial Haplogroup is Associated with Decreased Longevity in a Historic New World Population

Interest in mitochondrial influences on extended longevity has been mounting, as demonstrated by a growing literature. Such work has demonstrated that some haplogroups are associated with increased longevity and that such associations are population-specific. Most previous work however, suffers from the methodological shortcoming that long-lived individuals are compared with "controls" who are born decades after the aged individuals were. The only true controls of the elderly are people who were born on the same time period, but who did not have extended longevity. Here we present results of a study in which we are able to test if longevity is independent of haplogroup type, controlling for time period, by using mitochondrial DNA genealogies. Since mtDNA does not recombine, we know the mtDNA haplogroup of the maternal ancestors of our living participants. Therefore, we compare the haplogroup of people with and without extended longevity, who were born during the same time period.

Our sample is an admixed New World population which has haplogroups of Amerindian, European and African origin. We show that women who belong to Amerindian, European and African haplogroups do not differ in their mean longevity. Therefore, to the extent that ethnicity was tied in this population to mtDNA make up, such ethnicity did not impact longevity. In support of previous suggestions that the link between mtDNA haplogroups and longevity is specific to the population being studied, we found an association between haplogroup C and decreased longevity. Interestingly, the lifetime reproductive success and the number of grandchildren produced via a daughter of women with haplogroup C are not reduced. Our diachronic approach to the mtDNA and longevity link allowed us to determine that the same haplogroup is associated with decreased longevity during different time periods, and allowed us to compare the haplogroup of short and long-lived individuals born during the same time period. By controlling for time period, we minimize the effect of different cultural and ecological environments on differential longevity. With our diachronic approach, we investigate the mtDNA and longevity link with a biocultural perspective.

How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death.

On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders.

Mitochondrial pharmaceutics: A new therapeutic strategy to ameliorate oxidative stress in Alzheimer's disease

Association between amyloid-β (Aβ) toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage has been demonstrated in the pathophysiology of Alzheimer's disease (AD). In the early stages of the disease, the defect in energy metabolism was found to be severe. This may probably due to the Aβ and ROS-induced declined activity of complexes in electron transport chain (ETC) as well as damages to mitochondrial DNA. Though clinically inconclusive, supplementation with antioxidants are reported to be beneficial especially in the early stages of the disease. A mild to moderate improvement in dementia is possible with therapy using antioxidants.

Since mitochondrial dysfunction has been observed, a new therapeutic strategy called 'Mitochondrial Medicine' which is aimed to maintain the energy production as well as to ameliorate the enhanced apoptosis of nerve cells has been developed. Mitochondrial CoQ10, Szeto-Schiller peptide-31 and superoxide dismutase/catalase mimetic, EUK-207 were the mitochondrial targeted agents demonstrated in experimental studies. This article discusses the mitochondrial impairment and the possible mitochondria targeted therapeutic intervention in AD.

That last one is interesting for related reasons: it seems that efforts to selectively target antioxidants to mitochondria continue to spread on the basis of promising early results from some lines of development published over the past decade or so. There's a post back in the Fight Aging! archives on Szeto-Schiller peptide-31, and many of you probably know about the development of plastiquinones such as SkQ1.


There is a growing determination in some portions of the aging research community to obtain a formal classification of aging as a disease. This means different things to different people, and there are numerous independent regulatory or classification bodies involved in defining and declaring disease. It is a highly politicized process in wealthier regions of the world, tending to involve lining the pockets of politicians and, indirectly, their appointees and allies in regulatory agencies. It takes years to make any sort of progress - just look at ongoing efforts to have the age-related muscle loss known as sarcopenia defined as a disease rather than normal aging in the US regulatory system. That has been underway for nearly as long as I've been an advocate for this cause, with no end in sight, and at a cost of untold millions and wasted years that could have been spent on getting a treatment working and out there in the clinics.

The incentive is there for scientists and research institutions to have aging declared a disease because that opens doors to funding sources, and permits treatments aimed at controlling aging to run through the regulatory process at all. The FDA does not consider aging to be a medical condition at this time, and this position must change in order to allow any sort of meaningful development pipeline to form: everything that happens in cutting edge aging research today happens despite the fact that no-one is permitted to go out there and directly commercialize a treatment. As you might imagine that has a considerable damping effect on funding. I'd prefer change to involve tearing down the FDA and all similar bodies, but most people just want to see a little adjustment: to petition the powers that be until they grudging allow you just that little extra degree of freedom within the straitjacket.

Whether or not aging is a disease from the point of medical philosophy or dictionary definition is somewhat beside the point in comparison to issues of money and issues of freedom to act within the regulatory system. Not that this stops people from pouring on the philosophy, and any other argument to hand, in service of trying to change present regulation:

It is time to classify biological aging as a disease

Is aging a disease? Traditionally, aging has been viewed as a natural process and consequently not a disease. This division may have, in part, originated as a way of establishing aging as an independent discipline of research. Some authors go as far as to create a division between intrinsic aging processes (termed primary aging) and diseases of old age (termed secondary aging). For example, photoaging, the accelerated deterioration of skin as a result of UV rays during one's lifetime, is considered by dermatologists as a condition leading to pathology. In contrast, chronological skin aging is accepted as the norm. As well as being seen as separate from disease, aging is looked at as a risk factor for developing disease. Interestingly, the so-called "accelerated aging diseases" such as Hutchinson-Gilford Progeria Syndrome, Werner syndrome and Dyskeratosis Congenita are considered diseases. Progeria is considered a disease but yet when the same changes happen to an individual 80 years older they are considered normal and unworthy of medical attention.

Additionally, normal in a medical context is generally defined as no deviation outside of the normal reference range for that age and sex, whilst diseases are seen as deviation from this normal condition for that age and sex. Thus someone with a blood pressure of below 120/80 is seen as normal while a blood pressure above 140/90 or below 85/55 is abnormal and a sign of disease. The stratification of reference ranges for age is needed to distinguish fully developed adults from still developing children. Aging as the passage of time and the accumulation of wisdom is not undesirable; the physiological decline that accompanies the process, however, most certainly is.

Whilst aging is a nearly universal occurrence, it should be noted that other medical problems such as muscle wastage leading to sarcopenia, reduction in bone mass and density leading to osteoporosis, increased arterial hardening resulting in hypertension, atherosclerosis, and brain tissue atrophy resulting in dementia, all of which are nearly universal in humans, are classified as diseases in need of medical interventions. Also, autopsy studies indicate that amyloidosis may be almost universal in elderly people and, in autopsies performed by the Supercentenarian Research Foundation (SRF), amyloidosis has been identified as the cause of death in about 70% of people over 110 years of age. Should we remove amyloidosis from medical textbooks as an age-related disease just because it happens to occur in almost every elderly subject?

While most still seem to consider aging not to be a disease others have started to question this position. Some have argued that aging should be considered a disease, a syndrome or a 'disease complex'. Whilst many aging researchers have openly declared that the universality of the aging process means it is not a disease, aging fits the given medical definition of a disease. There is no disputing the fact that aging is a 'harmful abnormality of bodily structure and function'. What is becoming increasingly clear is that aging also has specific causes, each of which can be reduced to a cellular and molecular level, and recognisable signs and symptoms.

Researchers write: "In short, not only does aging lend itself to be characterised as a disease, but the advantage of doing so is that, by rejecting the seeming fatalism of the label 'natural', it better legitimises medical efforts to either eliminate it or get rid of those undesirable conditions associated with it". The goal of biomedical research is to allow people to be "as healthy as possible for as long as possible". Having aging recognized as a disease would stimulate grant-awarding bodies to increase funding for aging research and develop biomedical procedures to slow the aging process. Indeed, others have stated that calling something a disease involves the commitment to medical intervention. Furthermore, having a condition recognized as a disease is important to have treatment refunded by health insurance providers.

We believe that aging should be seen as a disease, albeit as a disease that is a universal and multisystemic process. Our current healthcare system doesn't recognize the aging process as the underlying cause for the chronic diseases affecting the elderly. As such, the system is setup to be reactionary and therefore about 32% of total Medicare spending in the Unites States goes to the last two years of life of patients with chronic illnesses, without any significant improvement to their quality of life. Our current healthcare system is untenable both from a financial and health and well-being prospective. Even minimal attenuation of the aging process by accelerating research on aging, and development of geroprotective drugs and regenerative medicines, can greatly improve the health and wellbeing of older individuals, and rescue our failing healthcare system.


If there is one sweeping generality to be made about cellular biochemistry, it is that everything is connected to everything else. No mechanism operates in isolation, and many areas of interest to aging research that have been studied point by point over the past few decades are all different aspects of the same larger system. This is becoming much more apparent in this age of powerful computers and advanced biotechnology: specialists can get more done with their time, and thus see more of the bigger picture within which their work rests. Today's example involves muscle aging, the dynamics of muscle stem cell populations, the role of the immune system in regeneration, and the response of muscle cells to exercise and other stresses. These three are all fairly large areas of study in and of themselves, but they overlap considerably as they are parts of a system in which everything is connected to everything else.

For a variety of reasons, of which the most important is probably nothing more than ease of access, muscle is one of the most studied of tissues. Certainly work on stem cell aging in muscle is a hot topic these days, and researchers are more capable of working with muscle stem cells than with most other types. By necessity this includes a greater knowledge of surrounding mechanisms and areas of research as well. Of particular interest in the paper linked below is the role of nitric oxide: if you look back into the Fight Aging! archives you'll find it shows up in many places in the biochemistry of aging tissues. It is near everywhere.

Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide

Aging muscle undergoes a shift in the balance between myogenic potential and fibrogenic activity so that senescent muscle suffers from a reduced capacity to repair and regenerate as it becomes increasingly fibrotic. Over time, the shift can lead to substantial accumulations of connective tissue. For example, recent findings show that the concentration of collagen in the muscles of old mice is nearly twice the concentration in young mice, corresponding to a twofold increase in muscle stiffness. Much is unknown concerning the mechanisms that drive senescent muscle toward fibrosis, but recent findings concerning fibrotic processes in dystrophic muscle or in wild-type muscle that has experienced acute injury indicate that the immune system can play important roles in regulating the balance between myogenesis and fibrosis.

Our findings show that muscle aging is associated with elevations of anti-inflammatory M2a macrophages that can increase muscle fibrosis. M2a macrophages promote muscle fibrosis by arginase-mediated hydrolysis of arginine that drives the production of ornithine that is then metabolized to produce proline required for collagen production. The amplified, profibrotic inflammatory response in injured or diseased muscle can be exacerbated by the loss of neuronal nitric oxide synthase (nNOS) from muscle. Nitric oxide (NO) generated by muscle nNOS serves many regulatory roles, but in the context of muscle inflammation, it plays a role in inhibiting extravasation of leukocytes into the damaged tissue. However, muscle-derived NO can also activate satellite cells, which are a population of muscle-specific stem cells that reside in fully differentiated muscle. Satellite cell activation is required for normal muscle regeneration and growth. Thus, loss of nNOS from dystrophic muscle shifts the myogenic/fibrotic balance toward fibrosis by loss of normal NO modulation of leukocytes and satellite cells.

Skeletal muscle aging also causes large reductions in the expression of nNOS that accompany the increase in fibrosis and the reduction in regenerative capacity experienced during muscle senescence. Thus, it is feasible that the age-related decrease in muscle nNOS expression contributes to an increase in the numbers and activation of leukocytes that promote muscle fibrosis while also leading to a reduction in the numbers of satellite cells, which would reduce the regenerative capacity of aging muscle.

We test that hypothesis in the present investigation by examining the effects of expressing a muscle-specific nNOS transgene on the numbers and phenotype of leukocyte populations in the muscle, the occurrence of fibrosis, and the prevalence of satellite cells in aging muscle. We also test whether age-related increases in macrophage populations in muscle are attributable to the age of the hematopoietic stem cell population from which they are derived, or reflect the age of the muscle in which they reside by performing heterochronic bone marrow transplantations (BMT) between young and old mice and analyzing the effects of those transplantations on muscle macrophage phenotype and fibrosis in old muscle.

Collectively, our data show that M2a macrophages in muscle increase with aging in association with increased fibrosis, and we find that preventing the reduction in nNOS expression in aging muscle prevents age-related changes in muscle macrophages and fibrosis, without affecting the prevalence of satellite cells. Our findings also show that the shift of muscle macrophages to an M2a phenotype is strongly influenced by the age of the hematopoietic cells from which they are derived.


Human life span is quite unusual in that it includes a prolonged post-reproductive period in females and the existence of menopause. This is observed in some other species in captivity, provided with the benefits of life-long veterinary care, but in the wild very few species indeed share this characteristic with us. Of these, killer whales are the nearest to us in the evolutionary tree of life. None of our closer relatives, such as other primates, experience menopause. They are in addition short-lived in comparison to our length of life. Chimpanzees and gorillas top out at 50-60 years of age in captivity, and a decade or more less in the wild.

Much of current thinking on the topic of unusual human longevity, at least when compared with our primate cousins, centers on our intelligence and capacity for culture as the originating difference. This allows older people to contribute materially to the success of their descendants, and this applies selection pressure to extended life: those with the capacity to live longer prosper, and some new balance of biological mechanisms is reached under the hood as a result. This view of the recent evolutionary past is known as the grandmother hypothesis, and ties together the existence of menopause, exceptional longevity, and the well-known disparity between male and female life spans. You can look back in the Fight Aging! archives for a pointer to a good open access paper on this topic.

You might consider the paper linked below as a reading companion to that earlier publication. The nature of longevity and its origins in our evolutionary past are very interesting topics. It doesn't have any great and immediate relevance to efforts to repair the causes of aging and thus indefinitely extend human life spans, of course. How and why we ended up in this situation isn't terribly important in comparison to understanding our present biology well enough to maintain it properly over time. I think you'll agree it is a good read nonetheless:

The evolution of prolonged life after reproduction

Why ageing occurs has been a central question in ecology and evolution for much of the past century. There is general agreement that the evolution of senescence is unavoidably linked to the fact that under natural conditions organisms die from extrinsic hazards. Since there are always fewer older individuals in a population than younger ones, the strength of selection on alleles with age-specific fitness effects is expected to weaken with increasing age and alleles that confer advantages early in life, by increasing early-life fecundity, can spread to fixation even if they have deleterious effects later. The declining strength of selection with age sets the stage for the evolution of physiological mechanisms leading to both reproductive and somatic senescence.

Somatic and reproductive senescence are inherently linked: there is no benefit to an organism in maintaining a viable germline if somatic senescence has progressed to the point that prevents successful reproduction. Most vertebrate species typically show a gradual decline in reproduction with age. However, in some circumstances reproductive senescence is accelerated relative to somatic senescence leading to a post-reproductive life span (PRLS). Why females of some species cease ovulation before the end of their natural lifespan is a longstanding evolutionary puzzle. Theoretical research over the past 50 years provides a coherent framework to understand senescence in general, but decoupling somatic and reproductive senescence has proved a major theoretical challenge.

PRLSs in modern humans are often dismissed as an artefact: medicine and the protected environments of the contemporary world allow women to live beyond the supply of primary oocytes. There is, however, considerable evidence that humans living with high rates of mortality and without access to modern medicine exhibit PRLSs. Others have argued that post-reproductive longevity is an epiphenomenon of antagonistic pleiotropy favouring early-life fertility at the expense of fertility later in life or that PRLSs have evolved as an insurance against the risk of dying by chance before the cessation of reproductive activity. There is, however, mounting evidence that in humans, resident killer whales, and social aphids post-reproductive females increase the survival or reproductive success of their kin. However, evidence that post-reproductive females increase the survival of kin is not sufficient to demonstrate that PRLSs are adaptive. It is also necessary to show that PRLSs results in a net inclusive fitness benefit. The difficulty in demonstrating inclusive fitness benefits of PRLSs via mother and grandmother effects has prompted a search for new adaptive explanations. The question of why prolonged life after the cessation of fertility has evolved in some species has not been fully answered.

Given that the capacity for post-fertility survival appears to be widespread, why are prolonged PRLSs restricted to just three vertebrate species? We suggest that understanding how females compete for reproduction and help their kin, and how the magnitude of these costs and benefits change across the lifespan, is fundamental to understanding variation across species in the evolution of PRLSs. We should expect females to forgo late-life reproduction only where doing so boosts the fitness of their kin and where helping is more effective if females are no longer reproducing themselves.


Monday, May 25, 2015

Damage to mitochondrial DNA is a consequence of the normal operation of cellular processes, and is one of the contributing causes of degenerative aging. It acts through a convoluted chain of circumstances to generate a population of malfunctioning cells that export harmful reactive molecules into surrounding tissue. Here, researchers provide evidence linking mitochondrial DNA damage, and consequent dysfunction, with the progression of glaucoma, a form of neurodegeneration causing blindness:

Glaucoma is a chronic neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Mitochondrial DNA (mtDNA) alterations have been documented as a key component of many neurodegenerative disorders. However, whether mtDNA alterations contribute to the progressive loss of RGCs and the mechanism whereby this phenomenon could occur are poorly understood. We investigated mtDNA alterations in RGCs using a rat model of chronic intraocular hypertension and explored the mechanisms underlying progressive RGC loss.

We demonstrate that the mtDNA damage and mutations triggered by intraocular pressure (IOP) elevation are initiating, crucial events in a cascade leading to progressive RGC loss. Damage to and mutation of mtDNA, mitochondrial dysfunction, reduced levels of mtDNA repair/replication enzymes, and elevated reactive oxygen species form a positive feedback loop that produces irreversible mtDNA damage and mutation and contributes to progressive RGC loss, which occurs even after a return to normal IOP.

Furthermore, we demonstrate that mtDNA damage and mutations increase the vulnerability of RGCs to elevated IOP and glutamate levels, which are among the most common glaucoma insults. This study suggests that therapeutic approaches that target mtDNA maintenance and repair and that promote energy production may prevent the progressive death of RGCs.

Monday, May 25, 2015

The proximate cause of the most visible symptoms of Parkinson's disease is the progressive loss of a small but vital population of dopamine-generating neurons. This loss happens to everyone, but for a variety of underlying reasons, not all of which are clear at this time, people with Parkinson's experience a more rapid loss of these cells. This is the case for many age-related medical conditions: they are a more rapid progression of a process that is in fact happening to all of us, and so the development of therapies is worth keeping an eye on. One approach to the treatment of Parkinson's disease is to attempt to restore the failing population of dopamine-generating neurons via some form of cell therapy, as demonstrated here in rats:

Parkinson's disease (PD) is considered the second most frequent and one of the most severe neurodegenerative diseases, with dysfunctions of the motor system and with nonmotor symptoms such as depression and dementia. Compensation for the progressive loss of dopaminergic (DA) neurons during PD using current pharmacological treatment strategies is limited and remains challenging. Pluripotent stem cell-based regenerative medicine may offer a promising therapeutic alternative, although the medical application of human embryonic tissue and pluripotent stem cells is still a matter of ethical and practical debate.

Addressing these challenges, the present study investigated the potential of adult human neural crest-derived stem cells derived from the inferior turbinate (ITSCs) transplanted into a parkinsonian rat model. Emphasizing their capability to give rise to nervous tissue, ITSCs isolated from the adult human nose efficiently differentiated into functional mature neurons in vitro. Transplantation of predifferentiated or undifferentiated ITSCs led to robust restoration of behavior, accompanied by significant recovery of DA neurons within the substantia nigra. ITSCs were further shown to migrate extensively in loose streams primarily toward the posterior direction as far as to the midbrain region, at which point they were able to differentiate into DA neurons within the locus ceruleus. We demonstrate, for the first time, that adult human ITSCs are capable of functionally recovering a PD rat model.

Monday, May 25, 2015

The Brain Preservation Foundation aims at advancing and validating the state of the art for preserving the fine structure of the human brain, containing the data of the mind. This is a goal of great value for the cryonics industry, and for the possible plastination industry that might arise to be its competitor. All too many people, billions, will die before the advent and widespread availability of working rejuvenation therapies, and it is madness that so little is done to preserve these individuals for a chance at a future life, given the present existence of technologies that can achieve this goal. But that is the world we live in, and one of many things it is worth trying to change.

The Brain Preservation Foundation runs a technology prize to help accelerate and publicize progress in preservation technologies. Here is a recent update on the current batch of competitors:

Brain Preservation Prize competitor Shawn Mikula has just published the first ever paper demonstrating how an entire mouse brain can be preserved at the ultrastructure level for electron microscopic (EM) imaging of its entire connectome. As is well known to all electron microscopists, the traditional protocol for preparing brain tissue for EM imaging only works for small pieces of tissue. The key problem has been that the mix of chemicals used to preserve (and stain) the lipid membrane of cells, is prone to precipitation and barrier formation within the tissue. This has limited high-quality ultrastructure preservation and staining to depths of just a few hundred microns thick. Dr. Mikula's paper shows that this can be overcome by adding a high concentration of formamide to the mix. According to his paper this is sufficient to completely eliminate barrier formation allowing for uniform preservation and staining of an entire mouse brain.

Are these results sufficient for Mikula to win the mouse phase of our Brain Preservation Prize? The short answer is yes - if the claims made in the paper can be verified by our imaging then Mikula will be awarded the mouse phase of our prize. Another key question is whether his 'formamide' technique will be able to be scaled up to a large mammal - like the pig brain required for the final phase of our prize, or a human brain? Dr. Mikula is already working to procure high-quality glutaraldehyde perfused pig brains on which to test his technique. I suspect that to scale up to these large brains his protocol will need to be modified to include vascular perfusion.

I want to also touch on the significant progress that has been made by our other competitor team, 21st Century Medicine (21CM). 21CM's core mission is to develop a cryopreservation protocol sufficiently benign that whole, donated human organs could be vitrified (stored below -130 degrees Celsius without ice formation) and rewarmed when needed for transplantation. They have had great success showing that viability can be restored in vitrified slices of tissue. Unfortunately it is much easier to get cryoprotectant solutions into and out of half millimeter slices than whole brains. The whole rabbit brains that 21CM has perfused with cryoprotectant agents (CPA) for our prize have shown significant amounts of shrinkage due to dehydration from the high concentration and fast ramping of CPA used. Electron micrographs of this tissue are thus difficult to interpret and we have been unable to accurately assess the degree of ultrastructure preservation by this technique. 21CM has ideas on how to overcome this hurdle (which they believe to be one of evaluation rather than preservation) but progress has stalled on those experiments due to the expense involved.

Recently however, 21CM has begun a set of experiments which overcomes this dehydration and shrinkage issue in a very simple and inexpensive, but unorthodox, way. They perfuse the rabbit brain with glutaraldehyde fixative prior to perfusion with CPA and low temperature vitrification! This pre-fixation is of course completely incompatible with recovery of function by simple rewarming, but it has the effect of stabilizing the vascular system and tissue sufficiently to allow long duration room temperature perfusion of CPA. Initial results show that these brains (stored intact briefly at -135 degrees C) are not shrunken by this procedure and electron micrographs of brain ultrastructure appear "textbook-normal".

Tuesday, May 26, 2015

The amount of visceral fat carried by individuals, just like number of calories consumed, has a strong influence on natural variations in health and longevity. More visceral fat is a bad thing, producing chronic inflammation and other less well understood disruptions of metabolism. This study shows that men, but not women, in long-lived families are less fat. That this is the case for only one gender is some defense against the hypothesis that the important factor being passed down here is culture (choosing to eat less) rather than genes, which would put a damper on many claims of genetic associations in longevity.

If the case, this would be an analogous situation to many life span studies in mice in recent decades that failed to control for inadvertent calorie restriction, and thus mistakenly identified various interventions as being life-extending, when in fact it was simply a matter of reduced calorie intake. The consequences of differences in visceral fat tissue, like those of dietary calorie intake, are large in comparison to most other influences on long term health at the present time, and so caution should be the watchword. Read studies carefully.

Familial longevity is marked by an exceptionally healthy metabolic profile and low prevalence of cardiometabolic disease observed already at middle age. We aim to investigate whether regional body fat distribution, which has previously shown to be associated with cardiometabolic risk, is different in offspring of long-lived siblings compared with controls.

Our institutional review board approved the study, and all participants (n = 344, average age in years 65.6) gave written informed consent. Offspring (n = 175) of nonagenarian siblings were included. Their partners (n = 169) were enrolled as controls. For abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) measurements, a single-slice 8.0 mm computed tomography (CT) acquisition was planned at the level of the 5th lumbar vertebra. In addition, participants underwent prospectively electrocardiography-triggered unenhanced volumetric CT of the heart. Abdominal VAT and SAT areas and epicardial adipose tissue (EAT) volumes were acquired. Linear regression analysis was performed adjusting for cardiovascular risk factors.

Total abdominal fat areas were smaller in male offspring compared with controls (353.0 versus 382.9 cm2). The association between low abdominal VAT areas in male offspring (149.7 versus 167.0 cm2 in controls) attenuated after additional adjustment for diabetes. Differences were not observed for females. EAT volumes were similar between offspring of long-lived siblings and controls. We conclude that males who have genetically determined prospect to become long-lived have less abdominal fat and in particular less abdominal VAT compared with controls.

Wednesday, May 27, 2015

In the past researchers have shown that reprogramming adult cells to create induced pluripotent stem cells sweeps away some specific forms of damage observed in old cells. In particular it seems to clean up damaged mitochondria, which is of considerable interest given the role of mitochondrial DNA damage in aging. It is possible that this has some connection to the aggressive cleanup that takes place in early stage embryos, stripping out damage inherited from parental cells. There may be the basis for a future therapy somewhere in here, but is also possible that finding out how to apply this sort of process in isolation to adult cells safely is going to be very hard, and the end result impractical in comparison to other technologies: if induced pluripotency as it currently stands somehow happened to many of your cells, you would certainly die.

I've linked to the open access paper rather than the publicity materials because I think that the latter are misleading as to what was accomplished and the significance of the research. The researchers theorize that the ability to restore mitochondrial function, and then break it again when you take the induced pluripotent stem cells and redifferentiate them back into ordinary cells, means that mitochondrial DNA damage is not a primary source of harm, but rather something under the influence of the state of nuclear DNA and thus some other cell process. For example, perhaps epigenetic changes in nuclear DNA are mediating the pace of replication-induced DNA damage in mitochondria.

All in all it is interesting work, and programmed aging supporters, who theorize that aging is largely caused by epigenetic changes, will no doubt find it encouraging, though I think that at this stage there are other possible interpretations of what is taking place here. For example, in how reprogramming restores function and how that function is lost again: one could proposed clearance and damage mechanisms rather than direct regulation mechanisms. The researchers are in most circumstances looking at mitochondrial function (via oxygen consumption rates) rather than at mitochondrial DNA damage, which greatly muddies the water. The two do not have a straightforward relationship, and there are any number of simple drug treatments that can tinker with the results of measures of mitochondrial function without touching the issue of damage. I'd like to see the same work done again with mitochondrial DNA damage assessments at each stage and each intervention, and also animal studies rather than just cell line studies in the case of the interventions in ordinary aged cells - which seems to be where this research group is heading in any case:

Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. Our previous studies proposed that the age-associated respiration defects found in human fibroblasts are caused not by mtDNA mutations, but by nuclear-recessive mutations. However, these findings can also be explained by assuming the involvement of epigenetic regulation of nuclear genes in the absence of nuclear-recessive mutations. Here, we addressed these controversial issues by reprogramming fibroblasts derived from elderly human subjects and examining whether age-associated mitochondrial respiration defects could be restored after the reprogramming.

In the case of epigenetic regulation, expression of mitochondrial respiration defects would be reversible and restorable with reprogramming. To examine this possibility, we randomly chose two young fibroblast lines and two elderly fibroblast lines and used them to generate human induced pluripotent stem cells (hiPSCs). These cells were then redifferentiated into fibroblasts and their mitochondrial respiratory function examined. We reprogrammed human fibroblast lines by generating iPSCs, and showed that the reprogramming of fibroblasts derived from elderly subjects restored age-associated respiration defects.

We also showed that age-associated mitochondrial respiration defects were expressed in the absence of either reactive oxygen species overproduction in the mitochondria or the accumulation of somatic mutations in mtDNA. One explanation for the absence of an age-associated increase in somatic mutations in mtDNA is the presence of a dynamic balance between the creation and segregation of somatic mutations in mtDNA during repeated cell division. This absence could also be a consequence of the preferential growth of cells possessing mtDNA without somatic mutations during repeated division of the primary fibroblasts obtained by biopsy. Here, however, our focus was on the causes of respiration defects expressed in elderly human fibroblast lines, and respiration defects were still expressed even after repeated divisions of cells from the primary biopsy samples. The question that then arises is: What causes age-associated mitochondrial respiration defects by epigenetic regulation?

Our findings revealed that epigenetic downregulation of nuclear-coded genes, including GCAT and SHMT2, which regulate glycine production in mitochondria, results in respiration defects. Our previous studies showed that the age-associated respiration defects in elderly fibroblasts are likely due in part to reduced translation activity in the mitochondria, but not in the cytoplasm. Therefore, defects in glycine metabolism in the mitochondria as a result of a reduction in SHMT2 and GCAT expression would be partly responsible for the reduction in mitochondrial translation, resulting in the expression of age-associated respiration defects. Because continuous glycine treatment restored respiration defects in elderly human fibroblasts, glycine supplementation may be effective in preventing age-associated respiration defects and thus benefiting the health of elderly human subjects. To confirm this hypothesis model mice deficient in GCAT or SHMT2, or both, would need to be generated to examine whether they expressed respiration defects and premature aging phenotypes and, if so, whether these disorders could be prevented by continuous glycine administration.

Wednesday, May 27, 2015

Here is a link to the presentation page for a recent BBC program on initiatives aiming to give us control over aging and death, with video clips on cryonics and SENS rejuvenation research:

We are in an era of disruptive technologies and innovation. Keeping resources, property and people safe and in good health, protected from the environment, disease and the passage of time are all imperative for mankind to thrive in the decades ahead. For instance some scientists think that we're close to a breakthrough in radically delaying ageing, if not halting it entirely. This comes at a time when life expectancy is increasing and there are ever more people on the planet.

Every innovation in healthcare also takes us a step closer to protecting more lives globally. But many tests are still decades old. Things are now changing. We're getting smarter at detecting disease earlier. We also have more powerful diagnostic tools. There has never been more potential to save people's lives. At this point in time we are now seeing an exponential growth in medical diagnostic and recording devices, our future physicians and doctors will be even more prepared for tomorrow's challenges.

In this series we look at those identifying the causes of ageing. We meet a world famous brain-trainer, who is looking at extending the life of our brains though exercises. Our reporters look at new affordable tests for pancreatic and liver cancers, as well as more efficient ways to detect disease from malaria to Hepatitis. From the developing to the developed world, innovation in the fields of protection are being democratised, barriers are coming down and allowing new discoveries to upset established norms. We have never been in an era of such exciting and disruptive potential.

Thursday, May 28, 2015

In recent years, researchers have provided evidence to suggest that cellular senescence mechanisms are partly involved in the decline of stem cell activity in aging. It is an open question as to how this interacts with other signaling mechanisms also recently shown to influence the suppression of stem cell tissue maintenance. This is one part of a larger discussion over the degree to which loss of stem cell activity is due to internal factors localized within the stem cell populations, such as cellular damage, or external factors such as changes in cell signaling systems that are a reaction to more widespread damage in tissues:

Regeneration of skeletal muscle relies on a population of quiescent stem cells (satellite cells) and is impaired in very old (geriatric) individuals undergoing sarcopenia. Stem cell function is essential for organismal homeostasis, providing a renewable source of cells to repair damaged tissues. In adult organisms, age-dependent loss-of-function of tissue-specific stem cells is causally related with a decline in regenerative potential. Although environmental manipulations have shown good promise in the reversal of these conditions, recently we demonstrated that muscle stem cell aging is, in fact, a progressive process that results in persistent and irreversible changes in stem cell intrinsic properties.

Global gene expression analyses uncovered an induction of p16INK4a in satellite cells of physiologically aged geriatric and progeric mice that inhibits satellite cell-dependent muscle regeneration. Aged satellite cells lose the repression of the INK4a locus, which switches stem cell reversible quiescence into a pre-senescent state; upon regenerative or proliferative pressure, these cells undergo accelerated senescence (geroconversion), through Rb-mediated repression of E2F target genes. p16INK4a silencing rejuvenated satellite cells, restoring regeneration in geriatric and progeric muscles. Thus, p16INK4a/Rb-driven stem cell senescence is causally implicated in the intrinsic defective regeneration of sarcopenic muscle. Here we discuss on how cellular senescence may be a common mechanism of stem cell aging at the organism level and show that induction of p16INK4a in young muscle stem cells through deletion of the Polycomb complex protein Bmi1 recapitulates the geriatric phenotype.

Thursday, May 28, 2015

Heat shock proteins such as HSP70 are molecular chaperones involved in cellular housekeeping processes that clear out damaged or misfolded proteins. Their activity increases in response to heat, toxins, and various other forms of cellular stress, and dialing up the activity of heat shock proteins is involved in a number of methods demonstrated to slow aging in laboratory animals. There are a few programs underway in the research community aimed at producing therapies that increase heat shock protein activity, especially for neurodegenerative conditions involving protein aggregates, but nothing that has yet made the leap into later stages of development and higher levels of funding:

Reducing the levels of toxic protein aggregates has become a focus of therapy for disorders like Alzheimer's and Parkinson's diseases, as well as for the general deterioration of cells and tissues during aging. One approach has been an attempt to influence the production or activity of a class of reparative chaperones called heat shock proteins (HSPs), of which HSP70 is a promising candidate. Manipulation of HSP70 expression results in disposal of misfolded protein aggregates that accumulate in aging and disease models. Recently, HSP70 has been shown to bind specifically to an amino-terminal sequence of a human diffusible survival evasion peptide (DSEP), dermcidin. This sequence includes CHEC-9, an orally available anti-inflammatory and cell survival peptide.

In the present study, we found that the CHEC-9 peptide also binds HSP70 in the cytosol of the cerebral cortex after oral delivery in normal rats. Western analysis suggested that peptide treatment increased the level of active HSP70 monomers from the pool of chaperone oligomers, a process that may be stimulated by potentiation of the chaperone's adenosine triphosphatase (ATPase). In these samples, a small but consistent gel shift was observed for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a multifunctional protein whose aggregation is influenced by HSP70. CHEC-9 treatment of an in vitro model of α-synuclein aggregation also results in HSP70-dependent dissolution of these aggregates.

HSP70 oligomer-monomer equilibrium and its potential to control protein aggregate disease warrant increased experimental attention, especially if a peptide fragment of an endogenous human protein can influence the process.

Friday, May 29, 2015

Of the many methods of slowing aging discovered to date most have only a small effect in short-lived species such as mice, around a 10% increase in healthy or maximum life span. Based on what we know of methods where we do have data for comparison, such as calorie restriction, these methodologies are expected to have even smaller effects in longer-lived species such as ourselves. Worth spending time on? Probably not. We need to chase after new and better biotechnology that can provide comprehensive repair of the damage that causes aging, not slight optimizations to our internal engines so that they wear out just a little bit more slowly.

Interestingly, many methods of modestly slowing aging in mammals such as mice have strongly gender-specific effects. This comes as part and parcel of the overall effect being small. Presently envisaged repair biotechnologies to treat aging and bring it under medical control will probably also have gender-specific differences in outcome or implementation to some degree, but these will be very small in comparison to the benefits provided:

A robust, often underappreciated, feature of human biology is that women live longer than men not just in technologically advanced, low-mortality countries such as those in Europe or North America, but across low- and high-mortality countries of the modern world as well as through history. Women's survival advantage is not due to protection from one or a few diseases. Women die at lower rates than men from virtually all the top causes of death with the notable exception of Alzheimer's disease, to which women are particularly prone. Yet, despite this robust survival advantage, women across countries of the world suffer worse health throughout life.

The biological mechanisms underlying either longer female survival or poorer female health remain elusive and understudied. Mechanisms of mammalian biology, particularly with respect to aging and disease, are most easily studied in laboratory mice. Although there are no consistent differences in longevity between mouse sexes even within single genotypes, there are often substantial differences in individual studies, sometimes favoring females, other times males. Investigating the environmental causes of this puzzling variation in longevity differences could prove illuminating.

Sex differences in response to life-extending genetic or pharmacological interventions appear surprisingly often in mice. Longevity enhancement due to reduced signaling through IGF-1 or mTOR signaling typically favors females, whereas enhancement via a range of pharmacological treatments favors males. These patterns could be due to interactions of the interventions with sex steroids, with adiponectin or leptin levels, or with the sex differences in immune function or the regional distribution of body fat. Clearly, generalizations from one sex cannot be extended to the other, and inclusion of both sexes in biomedical studies of human or other animals is worth the effort and expense.

Friday, May 29, 2015

Telomeres are the caps at the ends of chromosomes, shortening with each cell division in normal cells. When very short a cell self-destructs or falls into a senescent state and ceases further replication. Stem cells maintain long telomeres via the activity of telomerase, and provide fresh new long-telomere daughter cells to replace those lost over time in tissues throughout the body. Average telomere length in a cell sample is thus a reflection of stem cell activity and consequent cell replacement rates, as well as the pace of cell division. It is commonly measured in immune cells from a blood sample, and tends to fall during periods of ill health and be lower for older people. This should not be surprising given that stem cell activity declines with age, one of the contributing causes of frailty and failure of tissue function.

There are considerable limitations inherent in the interpretation of present telomere length measurement techniques, not least of which being the existence of studies such as this one in which study populations known to have longer life expectancies and better health do not demonstrate longer telomere length. It isn't hard to find work that challenges the relevance of this marker as a tool for everyday clinical medicine, or even as a basis for serious studies in aging, at least as presently measured:

A career as an elite-class male athlete seems to improve metabolic heath in later life and is also associated with longer life expectancy. Telomere length is a biomarker of biological cellular ageing and could thus predict morbidity and mortality. The main aim of this study was to assess the association between vigorous elite-class physical activity during young adulthood on later life leukocyte telomere length (LTL). The study participants consist of former male Finnish elite athletes (n = 392) and their age-matched controls (n = 207).

Relative telomere length was determined from peripheral blood leukocytes by quantitative real-time polymerase chain reaction. Volume of leisure-time physical activity (LTPA) was self-reported and expressed in metabolic equivalent hours. No significant difference in mean age-adjusted LTL in late life was observed when comparing former male elite athletes and their age-matched controls. Current volume of LTPA had no marked influence on mean age-adjusted LTL. LTL was inversely associated with age. Our study findings suggest that a former elite athlete career is not associated with LTL later in life.


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