Fight Aging!

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.

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.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424450/

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.

Link: http://dx.doi.org/10.1159/000381472

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.

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.

Link: http://dx.doi.org/10.1089/rej.2014.1620

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.

Link: http://dx.doi.org/10.4161/15384101.2014.965072

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.

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.

Link: http://www.bbc.com/specialfeatures/horizonsbusiness/seriesfive/episode-3-extending-lives/

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.

Link: http://dx.doi.org/10.1038/srep10434

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.

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.

Link: http://dx.doi.org/10.1093/ageing/afv063

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".

Link: http://blog.brainpreservation.org/2015/05/26/may-2015-bpf-prize-update/

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

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.

Link: http://dx.doi.org/10.5966/sctm.2014-0078

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.

Link: http://dx.doi.org/10.1016/j.nbd.2014.11.014

NPR recently ran a show interviewing a number of people who have given TED talks relating to aging, among them Aubrey de Grey, cofounder of the SENS Research Foundation and coordinator of rejuvenation research programs, and Cynthia Kenyon, whose work on single gene manipulations that extend nematode longevity back in the 1990s arguably kicked off the modern wave of interest in slowing aging. It makes for interesting listening; you should certainly take a little time and at least look at the transcripts.

In these short interviews you can see illustrated the most important division in the modern work aimed at intervention into the aging process: on the one hand the mainstream approach of altering the operation of metabolism so as to slow down aging, based on traditional drug discovery methodologies, and on the other hand the radical, disruptive approach of repairing the damage caused by the normal operation of metabolism, requiring the development of new biotechnologies. The strategy here is to avoid changing the operation of metabolism, because that is very hard and far too little is known of the important details, but rather periodically clean up the consequences of normal metabolic activity in order to prevent that damage from overwhelming and altering biological systems so as to cause degenerative aging.

As I'm sure all of you know by now, I'm greatly in favor of the latter approach because all the signs suggest it should be far more efficient and effective at extending healthy life spans, not to mention producing actual rejuvenation in the old. You can't greatly help the old by slowing down aging: better technologies are needed. Rejuvenation is needed. You can't bring aging under medical control by working on metabolic alteration to slow aging. Repair is needed, not merely dialing down the pace of new damage.

How Do You Make An Elderly Worm Feel Young Again?

Have you ever wanted to stay young a little longer and put off aging? This is a dream of the ages, but scientists have for a long time thought this was just never going to be possible. They thought, you know, you just wear out - there's nothing you can do about it, kind of like an old shoe. But if you look at nature, you see that different kinds of animals can have really different life spans. Now, these animals are different from one another because they have different genes. So that suggests that somewhere in these genes, somewhere in the DNA, are genes for aging, genes that allow them to have different life spans. So if there are genes like that then you can imagine that if you could change one of the genes in an experiment, an aging gene, maybe you could slow down aging and extend life span. And if you could do that then you could find the genes for aging, and if they exist, and you can find them then maybe one could eventually do something about it.

You would think to extend the life span of an animal for such a long time, you know, you'd have to kind of go around in a way and fix things or shore them up. You'd have to do something for the skin and something for the intestine, something for the nervous system. You'd have to - it would be really hard because old tissues all look old, but they all have their own separate problems. But what's the big surprise is that there are these systemic or system-wide control circuits that you can tap into. And what happens is that there are circulating factors, factors in the blood that can move through the animal and tell all the tissues to slow down their aging. Not to slow down their movement, but to slow down their aging. The great secret of all this is that, you know, all animals are much more similar to one another than they are different. Worms have muscles, they have nerve cells, they have serotonin, they have acetylcholine, they have all the neurotransmitters we have, the very same ones. So what that means is, you can easily interrogate the genome by making mutations to find genes that control things, things that you didn't even know were controlled, like aging. And there are actually hints that gene changes in humans that mimic the effects of these changes in animals may contribute to exceptional longevity to becoming a centenarian, in a human.

Can Aging Be Cured?

RAZ: And we just heard from Dan Buettner. He's an explorer and a researcher who studies Blue Zones. These are the areas of the world where people live much longer than anywhere in the...

AUBREY DE GREY: Well, let me stop you right there. How much? How much? It's very important to look at the numbers here.

RAZ: Aubrey de Grey would argue the handful of extra years you can get from, say, a Blue-Zone lifestyle is really pretty minor.

DE GREY: People often laugh at the U.S.A. on this kind of thing because the U.S.A. spends far more money per capita on healthcare than any other country in the world.

RAZ: Right.

DE GREY: And yet, if you look at the league table of life expectancy, it comes down in the 40s somewhere - like, 45 or whatever. But then if you look at the actual absolute numbers, the difference in lifespan between the U.S.A. and the number-one country, Japan, guess what it is? Just guess. Go on.

RAZ: I don't know - four years, five years.

DE GREY: Indeed, only four years. So you know - and these Blue Zones, you know, they might get another couple of years, but you know, the numbers are so small that we've got to do something that nobody has today.

RAZ: Aubrey is an Evangelist, probably one of the loudest voices for what might be described as the anti-aging movement. He's one of the leaders of a group called the SENS Research Foundation. It funds research into what he calls rejuvenation biotechnologies.

DE GREY: Which means new medicines that don't yet exist that will be able to repair the various types of molecular and cellular damage that the body does to itself throughout life and that eventually contribute to the ill health of old age.

RAZ: Aubrey basically looks at the human body in the same way he sees any other machine. You keep it oiled. You replace parts. You do preventative maintenance, and the machine can keep going a lot longer than it was ever meant to. So instead of just focusing on, say, a cure for cancer, he wants researchers to channel their energy into finding ways to prevent cancer and other diseases from ever developing in the human body in the first place. And he thinks if we could do that...

DE GREY: Basically, the types of things you could die of at the age of a hundred or 200 would be exactly the same as the types of things that you might die of at the age of 20 or 30.

RAZ: An accident, for example.

DE GREY: Exactly.

RAZ: Alzheimer's, dementia, cancer - these diseases occur because as you age, your body gets damaged. Molecules get damaged. Cells mutate. Junk accumulates in your body. All of this is natural. It happens to everyone. And Aubrey believes that that damage can be grouped into seven different categories, all of which could be prevented or at least slowed down.

DE GREY: So for illustration, let me just talk about one category.

RAZ: Sure.

DE GREY: Cell loss - what is cell loss? It's simply cells in a particular organ or tissue dying and not being automatically replaced by the division of other cells. Now, it turns out that that is actually an important contributor to certain aspects of aging - Parkinson's disease, for example. Now, the thing is, we know what the fix for that one is. We know that the right way to repair that kind of damage is stem cell therapy. Now, progress in that area has been patchy over the past 20 years that people have been thinking about this. But now, it's going really well. There are a couple of clinical trials going on. And I'm really optimistic. I think most people are very optimistic. I would say that we've got a very good chance of actually totally curing Parkinson's disease with stem cells in the next 10 years, even.

RAZ: But you're arguing that the right investment in certain scientific research couldn't just get us to a hundred or 110, but it could get us to 110, playing tennis.

DE GREY: That's exactly right - in fact, keeping up with your granddaughter on the dance floor.

RAZ: Is that going to happen?

DE GREY: Well, I've just told you it would. You sound as though you don't quite believe me.

RAZ: I do, but you can understand why it still, today, in 2015, sounds like science fiction, right?

DE GREY: Things that are only - have only a 50 percent chance of happening in 20 years from now are supposed to sound like science fiction.

Neural plasticity, the ability of the brain to generate new neurons and reshape its pathways, declines with age. Finding ways to temporarily reverse this decline and induce a more youthful state of plasticity may prove helpful in treating many conditions, but research is still at a fairly early stage of exploration:

Researchers have successfully re-created a critical juvenile period in the brains of adult mice. In other words, the researchers have reactivated brain plasticity - the rapid and robust changes in neural pathways and synapses as a result of learning and experience. The scientists achieved this by transplanting a certain type of embryonic neuron into the brains of adult mice. The transplanted neurons express GABA, a chief inhibitory neurotransmitter that aids in motor control, vision and many other cortical functions. Much like older muscles lose their youthful flexibility, older brains lose plasticity. But in the study, the transplanted GABA neurons created a new period of heightened plasticity that allowed for vigorous rewiring of the adult brain. In a sense, old brain processes became young again.

In early life, normal visual experience is crucial to properly wire connections in the visual system. Impaired vision during this time leads to a long-lasting visual deficit called amblyopia. In an attempt to restore normal sight, the researchers transplanted GABA neurons into the visual cortex of adult amblyopic mice. "Several weeks after transplantation, when the donor animal's visual system would be going through its critical period, the amblyopic mice started to see with normal visual acuity." These results raise hopes that GABA neuron transplantation might have future clinical applications. This line of research is also likely to shed light on the basic brain mechanisms that create critical periods.

Link: http://news.uci.edu/press-releases/uci-neurobiologists-restore-youthful-vigor-to-adult-brains/

Stem cell therapies to repair heart damage were one of the first to become widely available via medical tourism, and have been underway in earnest for more than a decade now. There is evidence from their use that benefits can be attained for patients. Providers and researchers continue to refine their techniques. There are numerous studies. That evidence is not good enough for the conservative end of the scientific community, who require a complete and rigorous understanding of the mechanisms of action before proceeding with enthusiasm, and nor for regulatory bodies in the US and Europe. Thus trials continue, now into their late stages, and treatments remain unavailable in many countries:

Like any new branch of medicine, cardiac cell therapy has progressed in fits and starts. Despite dozens of clinical trials, there's no slam-dunk treatment for improving the cardiac function of heart failure patients, but marginal, statistically significant improvements observed in some of the studies are propelling the cell-based therapies to ever larger, more expensive, and more rigorous trials. Most cardiologists remain underimpressed, says the head of an ongoing Phase 3 trial in Europe that involves injecting bone marrow cells into heart attack patients. "If [the trial] is positive, that's great, but I still think we'll have quite a challenge to convince people. If it's negative, then you get most of the cardiac community saying, 'Yep, we expected that.'?"

Now, it's make or break. Some anticipate that the results of the trial and two other ongoing Phase 3s will finally provide definitive evidence supporting the efficacy of cell therapies for the heart - evidence that has so far been lacking. On the other hand, negative results could spell the end of the approach altogether. "If our Phase 3 doesn't work, I think there's little likelihood any program could succeed in this indication," says the CEO of a Belgium-based firm sponsoring a clinical trial involving bone marrow-derived cells. "In the event they don't work [this time], I think it will be the end."

The idea to pluck cells from a person's bone marrow and shoot them into the heart took root in 2001, when researchers showed that doing so in mice could help regenerate damaged heart tissue. Yet no one knew how the cells worked. At the time, the prevailing thought was that stem cells took up residence in the heart and proliferated to produce new tissue. But this idea has since become a matter of debate. While some researchers claim the cells can form new cardiac muscle, others assert that the cells only very rarely differentiate into cardiomyocytes and instead support cardiac regeneration by other means.

Many scientists now believe that the introduced cells perform a paracrine function, signaling the activation of reparative pathways via growth factors or other secreted messengers. On its own, the heart regenerates about one percent of its tissue per year via the division of cardiomyocytes; perhaps cell therapies simply boost that normal behavior. The absence of a concrete mechanism of action has been one of the main criticisms of the field. On the other hand, most patients don't care how a treatment works, just that it does. "We have more trials than we have meaningful basic science papers. You'd like it to be the other way round. But I understand why there was an explosion [of clinical trials] - because there is such a need." And many researchers disagree that a known mechanism is required for advancing the therapy. "Nothing moves a field forward like actual clinical trials." While mechanisms are important - knowing them can help optimize treatments, for instance - "you can't slow things down because the mechanism of action isn't agreed upon by everybody."

Link: http://www.the-scientist.com/?articles.view/articleNo/42842/title/Hearts-on-Trial/

Changing the world is an activity built atop a foundation of persuasion and relationships, whether is a matter of creating entirely new technology or ensuring the widespread use of existing technologies. It always moves more slowly than advocates would like, even when things are progressing well, such as at the present time with regard to the public view of research into the effective treatment of aging. The past couple of years have seen a real transition in public perception and media treatment of aging research, the result of more than a decade of hard work and investment behind the scenes, all largely unnoticed. There are never any breakthroughs or sudden sweeping reversals in life: it is all a matter of the pieces finally falling into place, of the finale to a play that you just weren't paying all that much attention to while it was taking place.

The great revolution of our era is the plummeting cost and increasing capacity of computation. That has enabled all of the other transformative revolutions presently underway, such as in the cost, capabilities, and availability of communications technology and biotechnology. In communication especially, the cost of near instantly delivering old-style text from one person to another has fallen so far as to be essential zero, minuscule in comparison to the opportunity cost of time taken in composition of the message. Similarly, the cost of publishing to an audience has fallen to be essentially zero in comparison to the cost of finding that audience.

It is no coincidence that advocacy for longevity research, just like every goal originally held by a tiny fraction of the populace, has taken off in parallel with the growth of the internet. Beforehand, how were the one in a hundred or one in a thousand interested enough to talk and do something ever going to find one another? Now a special interest group of just a few hundred or few thousand people can span the globe and yet still be organized and effective, and for next to no cost beyond the time taken to participate. This is ideally suited to non-profit and advocacy organizations, and the last few decades of initiatives relating to extending the healthy human life span have seen many such organizations assemble via connections made online.

In this sense social media, a term I detest, means nothing more than communication. Everyone today has a near-zero-cost printing press and mail room. When everyone can act as their own newspaper, most people will do just that. Most of the resulting output is trivial, of course, because most conversations are trivial. But of those who have something to say that is worth listening to, more of that message will find a willing audience rather than being lost to the void. Of course there is always a power law of attention, there are always the professionals sitting on top of the pyramid, but ultimately we are expanded and improved by our new capabilities, each of us our own media outlet.

There are always those who mistake the shell for the snail, however. You can't force a conversation, or indeed any sort of meaningful outcome, by turning a crank and sending links here and there aimlessly, by counting posts and metrics. If there is no conversation, all of those mechanical actions, "social media activity", are just hollow. In all of my experiments in that, and all of the other experiments I've had the dubious pleasure of watching in the course of gainful employment as a technologist, I've become convinced that the only thing to do is have conversations. Talk to people. Publish what you want, and let people talk about it at the pace they want to talk about it. You can't force growth in advocacy, and it's really hard to measure where exactly you are in that process with the tools that social media companies force upon you. Advocacy for a cause doesn't have conversions and funnels that can be measured on a website or in an email, no matter what those selling you metrics engines might say. You end up with a lot of numbers and no real way to connect those numbers to anything that actually matters as a bottom line. So why try? There are share buttons here at Fight Aging!, hidden, not loaded at all until you request the tool, because people kept asking for them, not because I'm hot on creating larger numbers in a report.

So: we live in an age of ever more pervasive communication. That is important, very important, to all endeavors, and in ways that we haven't yet figured out. A lot of the more active members of the longevity science advocacy community are engaged in trying out new modes of organization and communication, building the community, present in ever new form of social media. But this is all, ever and always, at heart a conversation. It goes at its natural pace. We shouldn't forget that just because the tools of the trade are shiny and in everyone's hands these days.

Longevity online: can social media take life extension ideas from the radical to the mainstream?

To confront death is to face our biggest fear, and unfortunately for advocates of life extension, this is something which the majority of people are not presently inclined to do. Like any industry, the level of investment in life extension technologies and the resultant supply of treatments are directly related to demand. Therefore, for governments, scientific institutions, and venture capitalists to invest within the field, the demand from consumers simply has to be there. Recent big budget ventures spearheaded by some of Silicon Valley's most high profile companies and individuals go a long way to speeding up the rate of research and development as well as raising awareness of the cause, but for those looking to really accelerate the rate of progress, the question is how to get enough of the population onboard to significantly impact upon the rate of change.

In the 21st Century, social media has emerged as by far the most efficient and accessible platform for engagement between like-minded individuals, promoting shared ideas, and ultimately mobilising the general population into action. In fact, in our increasingly globalised world, such is the centrality of social media and its capacity to facilitate instant worldwide communication, one can argue that without it any movement or form of promotion is likely doomed to fail.

As a characteristically tech-minded community, it is therefore no surprise that the power of networks such as Facebook, Twitter, Google+, Linkedin, and Reddit as tools for furthering the cause of life extension has not been lost upon its most engaged advocates. One only has to peruse the most popular channels Facebook and Twitter to find literally hundreds of groups and profiles dedicated to life extension and longevity, with thousands of members based all over the world. Such high-levels of activity, one would assume, can only be a good thing for the life extension movement, but in terms of really taking life extension ideas from the radical to the mainstream, how far does social media currently go?

Cryonics is the industry and collection of technologies associated with low-temperature preservation of an individual upon death, necessarily carried out as soon as possible so as to prevent tissue damage in the brain. It is connected to research and development in forms of organ preservation associated with transplant medicine. A good cryopreservation of at least the brain ensures the best chance of future restoration with all the data of the mind intact, encoded in the fine structure of neurons and synapses: a preserved individual has all the time in the world to wait, after all. The odds of success are unknown, but infinitely better than is the case for all of the alternative options for those too old or too ill to wait for the advent of future rejuvenation therapies.

In an ideal world a good preservation would occur because it was scheduled ahead of time: a team and resources must be assembled and on the site, and this is hard and expensive to do at very short notice when there are so few qualified individuals and such a large territory to cover. This is why cryonics is strongly connected to legal issues surrounding self-determination in end of life choices, since in most countries people are forbidden to choose the time and manner of their own death, and doctors are forbidden to assist in enabling that death to be an easy one when the patient is in pain and dying, beyond the capacities of present medical technology. In that ideal world, the cryonics industry would also be large enough to ensure that first responders to medical emergencies, coroners, and other relevant individuals would as a matter of course be trained to understand and respect cryonics arrangements.

The present small size of the cryonics industry and the hostile nature of our legal systems means that we don't live in that world, unfortunately. We are not granted ownership over our own lives and bodies. Cryonics must occur as a last minute emergency effort at short notice in most cases, and the existing services and regulatory bodies must often be fought at the same time. Even people well connected within the cryonics community, who are well aware of the hurdles in the way, can succumb to sheer accident and as a result obtain a poor preservation with an unknown but probably large level of neural damage:

Dr. Laurence Pilgeram, a cryopreservation member of Alcor since 1991, was involved in cryonics early on. He gave a talk at the 1971 Cryonics Conference in San Francisco, California, on "Abnormal in-Vitro Oxidation and Lypogenesis Induced by Plasma in Patients with Thrombosis". Dr. Pilgeram was awarded his PhD. in Biochemistry at the University of California at Berkeley in 1953. In 1954-55 he served as an Instructor in Physiology at the University of Illinois College of Medicine in Chicago. After two years, he accepted an offer to develop and head an Arteriosclerosis Research Laboratory at the University of Minnesota School of Medicine. He later moved to Santa Barbara, California for a time before joining the Baylor College of Medicine in Houston, TX to develop and head the Coagulation Laboratory there.

On April 10, Dr. Pilgeram, collapsed outside of his home of an apparent sudden cardiac arrest. Despite medical and police personnel aware of his Alcor bracelet, he was taken to the medical examiner's office in Santa Barbara, as they did not understand Alcor's process and assumed that the circumstances surrounding his death would pre-empt any possible donation directives. Since this all transpired late on a Friday evening, Alcor was not notified of the incident until the following Monday morning.

Fortunately, no autopsy was performed which at least eliminated any invasive damage but the lengthy delay led to a straight freeze as the only remaining option. The medical examiner released the body to the mortuary that Alcor uses in Buena Park, California and he was immediately covered with dry ice, per our request. Aaron Drake and Steve Graber traveled to California to perform a neuro separation in the mortuary's prep room and then returned to Arizona for continued cool down which began on April 15, 2015.

Link: http://www.alcor.org/blog/dr-laurence-pilgeram-becomes-alcors-135th-patient-on-april-15-2015/

Any proposed first generation rejuvenation toolkit of future decades must include a robust approach to cancer therapy, at the very least offering reliable detection methods and cures even if not providing outright prevention. An important part of cancer therapies presently under development is the ability to far more accurately target cancer cells, thereby greatly reducing the presently onerous, damaging side-effects of treatment. Of the numerous approaches to targeted therapies, immunotherapy is one of the most advanced towards widespread clinical adoption, as illustrated by the results of this early stage trial of a form of adoptive T cell therapy:

Researchers say they have safely used immune cells grown from patients' own bone marrow to treat multiple myeloma, a cancer of white blood cells. A trial was conducted involving a particular type of tumor-targeting T cell, known as marrow-infiltrating lymphocytes (MILs). "What we learned in this small trial is that large numbers of activated MILs can selectively target and kill myeloma cells." MILs are the foot soldiers of the immune system and attack foreign cells, such as bacteria or viruses. But in their normal state, they are inactive and too few in number to have a measurable effect on cancer.

For the clinical trial, the team enrolled 25 patients with newly diagnosed or relapsed multiple myeloma, although three of the patients relapsed before they could receive the MILs therapy. The scientists retrieved MILs from each patient's bone marrow, grew them in the laboratory to expand their numbers, activated them with microscopic beads coated with immune activating antibodies and intravenously injected each of the 22 patients with their own cells. Three days before the injections of expanded MILs, patients received high doses of chemotherapy and a stem cell transplant, standard treatments for multiple myeloma.

One year after receiving the MILs therapy, 13 of the 22 patients had at least a partial response to the therapy, meaning that their cancers had shrunk by at least 50 percent. Seven patients experienced at least a 90 percent reduction in tumor cell volume and lived, on average, 25.1 months without cancer progression. The remaining 15 patients had an average of 11.8 progression-free months following MILs therapy. None of the participants had serious side effects from the MILs therapy. The overall survival was 31.5 months for those with less than 90 percent disease reduction, but this number has not yet been reached in those with better responses. The average follow-up time is currently more than six years.

Link: http://www.eurekalert.org/pub_releases/2015-05/jhm-pct051915.php

Heterochronic parabiosis has become a growing line of research these past few years. It involves connecting the circulatory systems of two individuals, such as two laboratory mice, of different ages. Researchers have shown that the old mouse of the pair regains somewhat more youthful characteristics in stem cell activity, healing, neurogenesis, cardiac health and other aspects linked to tissue maintenance. It doesn't turn back the clock by more than a fraction, but the benefits are large enough in comparison to what can be achieved via other avenues in medical science for researchers to investigate further. An outcome of partial rejuvenation of function during parabiosis must be triggered by a different balance of factors that is present in youthful blood versus aged blood. Thus researchers conclude that some fraction of the decline in tissue maintenance and diminished stem cell activity that occurs in aging has signaling changes in the tissue environment as its proximate cause. The next logical path of action for the mainstream research community is to undertake a drug discovery program, aiming for treatments that can override age-related changes in signaling to at least some degree, and with minimal side-effects.

These age-related changes in the amount or type of proteins present in circulating blood are not a root cause. They are themselves most likely a reaction to the accumulating cellular and tissue damage that drives degenerative aging. So it is worth bearing in mind that any treatment focused on spurring greater stem cell activity by overriding the natural aged signaling balance is essentially a matter of pushing the accelerator on a damaged engine. These and other related studies in mice have not yet seen the potential threat of cancer that would be expected to arise from greater activity undertaken by damaged cells, but caution is still merited. It may well be the case that the evolved balance of stem cell decline is far from optimal, and researchers could turn the dial a way without producing a high risk of cancer or other issues as a result. The fastest way to find out is to try. Equally it would be nice to see more attention given to repairing the damage that causes aging rather than trying to compensate for the consequences one layer up while ignoring the damage entirely.

Researchers have recently reported another potential success for heterchronic parabiosis, claiming the identification of β-catenin signalling as important in age-related decline of bone regeneration. Note that while the popular press is focusing on the parabiosis portion of the research, the scientists involved also produced the same benefits with a more conventional transplant of young cells into an old individual. Given the recent news about GDF-11, however, it might be worth waiting a couple of years for firm confirmation and clarification of the mechanism involved before celebrating this advance.

Old Bones Can Regain Youthful Healing Power

Broken bones in older people are notoriously slow to heal. In studies using mice, researchers not only traced what signals go wrong when aged bones heal improperly, they also successfully manipulated the process by both circulating blood and transplanting bone marrow from a young mouse into an older mouse, prompting the bones to heal faster and better. The work builds on earlier research which identified an important role for a protein called beta-catenin in the healing process. The protein requires precise modulation for successful bone fracture repair. In older people, beta-catenin levels are elevated during the early phases of bone repair, leading to the production of tissue that is more like scar than bone, which is not good for bone healing.

Using mice as a surrogate for humans, the researchers found that they could manipulate beta-catenin levels by exposing older animals to the blood circulation of younger animals, essentially correcting the intricate formula necessary for healthy bone repair. "It's not that bone cells can't heal as efficiently as we age, but that they actually can heal if they are given the right cues from their environment. It's a matter of identifying the right pathway to target, and that's what's exciting about this work. The next steps are to figure out what's making beta-catenin go up in older adults, so that we can target that cause, and to explore drugs that can be used in patients to change beta-catenin levels safely and effectively."

Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin

The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals.

This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.

It is important in the development of the present and the next generation of stem cell therapies to have cheap, reliable access to patient-specific pluripotent stem cells on demand. These are the basic starting point for generating therapeutic cells of a specific type, and only pluripotent cells have the capacity to create cells of any type. This is why there there is so much interest in developing the technology of induced pluripotency, for example, by which any cell sample from a patient can be used to create pluripotent cells. Some researchers believe that adult tissues contain populations of pluripotent stem cells necessary to continued tissue maintenance over a lifetime. If the case, these would be a useful source of cells for cell therapies. These proposed cell populations are given various names by various different research groups, such as very small embyronic-like stem cells. There is still some debate over whether such pluripotent cell populations actually exist in adult tissues, and whether researchers are accurately characterizing their observations. Research continues, however:

The pancreas is one of three organs (besides lung and liver) with huge regenerative ability. Mouse pancreas has a remarkable ability to regenerate after partial pancreatectomy, and several investigators have studied the underlying mechanisms involved in this regeneration process; however, the field remains contentious. Elegant lineage-tracing studies undertaken over a decade have generated strong evidence against neogenesis from stem cells and in favor of reduplication of pre-existing islets. Ductal epithelium has also been implicated during regeneration. We recently provided direct evidence for the possible involvement of very small embryonic-like stem cells (VSELs) during regeneration after partial pancreatectomy in mice.

VSELs were first reported in pancreas in 2008 and are mobilized in large numbers after treating mice with streptozotocin and in patients with pancreatic cancer. VSELs can be detected in mouse pancreas as small-sized LIN-/CD45-/SCA-1+ cells (3 to 5 μm), present in small numbers (0.6%), which express nuclear Oct-4 (octamer-binding transcription factor 4) and other pluripotent markers along with their immediate descendant 'progenitors', which are slightly bigger and co-express Oct-4 and PDX-1. VSELs and the progenitors get mobilized in large numbers after partial pancreatectomy and regenerate both pancreatic islets and acinar cells.

In this review, we deliberate upon possible reasons why VSELs have eluded scientists so far. Because of their small size, VSELs are probably unknowingly and inadvertently discarded during processing. Several issues raised in the review require urgent confirmation and thus provide scope for further research before arriving at a consensus on the fundamental role played by VSELs in normal pancreas biology and during regeneration, aging, and cancer. In the future, such understanding may allow manipulation of endogenous VSELs to our advantage in patients.

Link: http://dx.doi.org/10.1186/s13287-015-0084-3

The path of scientific discovery is never direct, and if something appears simple in an investigation of biochemistry then it is perhaps time to wonder what was missed and when the other shoe will drop. In the past couple of years researchers have demonstrated improved health in aged mice through reactivation of stem cell activity via increased levels of GDF-11. The situation may well be more complex than first thought, however, as a second group is having issues replicating the effect. This work calls into question present hypotheses on the nature of the underlying mechanisms exhibited in previous work on GDF-11, and points to the need for a better and more complete analysis of what is going on under the hood. The observed improvements to health seen in past studies are not yet disputed, but clearly something is missing:

In 2013, a team found that levels of a protein called GDF11 decreased in the blood of mice as they grew older. When the researchers injected the protein into the heart muscle of old mice, it became 'younger' - thinner and better able to pump blood. Two subsequent studies found that GDF11 boosted the growth of new blood vessels and neurons in the brain and spurred stem cells to regenerate skeletal muscle at the sites of injuries. Those results quickly made GDF11 the leading explanation for the rejuvenating effects of transfusing young blood into old animals. But that idea was confusing to many because GDF11 is very similar to the protein myostatin, which prevents muscle stem cells from differentiating into mature muscle - the opposite effect to that seen.

Researchers set out to determine why GDF11 had this apparent effect. First, they tested the antibodies and other reagents used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11. When the team used a more specific reagent to measure GDF11 levels in the blood of both rats and humans, they found that GDF11 levels actually increased with age - just as levels of myostatin do. That contradicts what the former group had found. The researchers next used a combination of chemicals to injure a mouse's skeletal muscles, and then regularly injected the animal with three times as much GDF11 as the former team had used. Rather than regenerating the muscle, GDF11 seemed to make the damage worse by inhibiting the muscles' ability to repair themselves.

Researchers suggest that there could be multiple forms of GDF11 and that perhaps only one decreases with age. Both papers suggest that having either too much or too little GDF11 could be harmful. The more recent research group injured the muscle more extensively and then treated it with more GDF11 than the former group had done, so the results may not be directly comparable. "We look forward to addressing the differences in the studies with additional data very soon."

Link: http://www.nature.com/news/young-blood-anti-ageing-mechanism-called-into-question-1.17583

There is no doubt a special circle of hell reserved for an individual who allows twelve years or more to lapse before adding a comments feed to his or her blog. I imagine that Dante would find a lot to say about the sins of our modern technological society, were he alive to be given the chance, but I've never claimed that things move rapidly around here. It took me five years of talking about it to get to the one and only redesign in the history of this site, for example.

This update is fairly simple and prosaic. Individual comments now have anchors within a page, and are directly linked in the feed. Many of you have by now worked out that comments allow a little HTML for formatting, such as italics and bold elements, and automatically convert pasted URLs into links. That HTML will transfer through into the feed. You'll find the new comments feed at the following URL:

https://www.fightaging.org/comments.xml

The new feed is also mentioned in the help page for Fight Aging! feeds. I should say that this feed is really just a stopgap for now to make life easier for people who like to keep up with conversations here. I know you that all have far better things to spend your time on than speculatively reloading posts here to see if anything new has arrived, but that was pretty much the only option. You do still have to set up a feed monitor or reader to keep tabs on the situation if you are participating: it does require a little work on your part to keep up, but this is still an improvement over the recent past.

In the future I am planning to move Fight Aging! from its present aging and unsupported platform to a standalone WordPress deployment, but the timing of this depends upon my finding the necessary free time to devote to the project. A start has been made, a lot of the fiddly setup and deployment issues completed. Given the more than ten years of increasingly baroque additions and customization to the present Fight Aging! platform, I have to say that it isn't a straightforward migration at the application level, however. It will be worth it once done. When set up in WordPress I will have a lot more latitude to add all sorts of useful features, such as subscription to comment threads, better presentation of recent comments on the site, and other items that would be quite painful to attempt today.

It looks increasingly likely that the WordPress migration will not happen prior to this year's Fight Aging! fundraiser for SENS research programs, given that the first phase of the fundraiser will be underway in a matter of a few weeks from now. While the fundraiser is going on I will have higher priority items to tackle than the migration; while a comment feed is a poor substitute to be going on with for the moment, it is considerably better than the nothing that was in place prior to today.

It is becoming ever more common these days to see news of proof of concept work for the engineering of specific tissue structures throughout the body. Here is a recent example:

In developing tissue-engineered gut replacements the researchers use smooth muscle and nerve stem cells from human intestine to engineer innervated muscle sheets. The sheets are then wrapped around tubular chitosan scaffolds. The tubular structures were implanted just under the skin of rats for 14 days, a first step in assessing their performance. Researchers found that the implants developed a blood vessel supply and that the tube opening was maintained. In addition, the innervated muscle remodeled as the cells began the process of releasing their own materials to replace the scaffold. "It is the combination of smooth muscle and neural cells in gut tissue that moves digested food material through the gastrointestinal tract and this has been a major challenge in efforts to build replacement tissue. Our preliminary results demonstrate that these cells maintained their function and the implant became vascularized, providing proof of concept that regenerating segments of the gastrointestinal tract is achievable."

The group's second project, to engineer anal sphincters, also reached a new milestone with the successful implantation of the structures in rabbits. Sphincters are ring-like muscles that maintain constriction of a body passage, such as controlling the release of urine and feces. There are actually two sphincters at the anus - one internal and one external. A large proportion of fecal incontinence in humans is the result of a weakened internal sphincter.

To engineer the internal anal sphincters, researchers used a small biopsy from the animals' sphincter tissue and isolated smooth muscle cells that were then multiplied in the lab. In a ring-shaped mold, these cells were layered with nerve cells isolated from small intestine to build the sphincter. The mold was placed in an incubator, allowing for tissue formation. The entire process took about four to six weeks. The bioengineered sphincters mimicked the architecture and function of native tissue and there are no signs of inflammation or infection after implantation. The constructs demonstrated the presence of contractile smooth muscle as well as mature nerve-cell populations. The bioengineered sphincters restored fecal continence in the animals throughout the six-month follow-up period after implantation.

Link: http://www.wakehealth.edu/News-Releases/2015/Researchers_Make_Progress_Engineering_Digestive_System_Tissues.htm

Meaningful progress in cancer research in the decade ahead will emerge from strategies that can be applied to many different types of cancer: the same cost in time and money goes into development as building a treatment that is applicable to only one type, but the end result is vastly more effective and useful. The one commonality shared by all cancer cells is the ability to extend telomeres to permit uncontrolled cell replication past the normal limits. Take that away and the cancer fades. This is the SENS approach to preventing cancer by striking at the root, and the same strategy is emerging elsewhere in the research community. A variety of different approaches are under development, most focused on interfering in the activity of telomerase:

Approximately 85 percent of cancer cells obtain their limitless replicative potential through the reactivation of a specific protein called telomerase reverse transcriptase (TERT). Recent cancer research has shown that highly recurrent mutations in the promoter of the TERT gene are the most common genetic mutations in many cancers. TERT stabilizes chromosomes by elongating the protective element at the end of each chromosome in a cell. Scientists have discovered that cells harboring these mutations aberrantly increase TERT expression, effectively making them immortal.

Researchers have identified that the mechanism of increased TERT expression in tumor tissue relies on a specific transcription factor that selectively binds the mutated sequences. A transcription factor is a protein that binds specific DNA sequences and regulates how its target genes are expressed (in this case the gene that expresses TERT). Thus, the TERT mutations act as a new binding site for the transcription factor that controls TERT expression. The newly identified transcription factor does not recognize the normal TERT promoter sequence, and thus, does not regulate TERT in healthy tissue.

The team's work further showed that the same transcription factor recognizes and binds the mutant TERT promoter in tumor cells from four different cancer types, underscoring that this is a common mechanism of TERT reactivation. The identified transcription factor and its regulators have great potential for the development of new precision therapeutic interventions in cancers that harbor the TERT mutations. A treatment that would inhibit TERT in a targeted cancer-cell-specific manner would bypass the toxicities associated with current treatments that inadvertently also target TERT in normal healthy cells. The team is now conducting a variety of experiments designed to test whether inhibiting the transcription factor activity would not only turn down TERT expression, but might also result in selective cancer cell death.

Link: http://engineering.illinois.edu/news/article/11131

One of the challenges inherent in talking to the public about aging is that there are many well-popularized rare conditions that have the superficial appearance of accelerated aging or slowed aging, but are in fact nothing of the sort. Take progeria, for example: it is a comparatively simple genetic dysfunction that induces a great deal of cellular dysfunction and damage. Aging itself is a matter of specific forms of cellular dysfunction and damage, but any vaguely similar limiting of cell activities will produce some of the same outcomes, such as failure of tissue maintenance and a decline in organ function and integrity. Progeria patients die young from cardiovascular disease as a result of these issues, and appear prematurely aged. Yet the type of damage to cells that occurs in progeria has next to no role in normal aging, and vice versa, and the outcomes only appear similar at the large scale because the essential high level functions of tissue are disrupted in both cases. In fact the two conditions, progeria and aging, have nothing to do with one another, and it is probably the case that little learned in progeria research will be applicable in the treatment of normal aging.

This is a moderately complex set of ideas to explain in enough detail for it all to make sense to someone not versed in the underlying science. It takes a little time, and good explanations are all too often obscured by simplified media stories that talk about accelerated aging in ways that make sound like progress in progeria research is a direct and useful approach to learning about normal aging. Not the case at all, however.

Another example of the type that has been making the rounds in the media for the past few years is a rare developmental disorder in which the child does not develop: one individual lived for two decades while remaining an infant. The colloquial sense of the word "aging" includes growing up to adulthood as well as getting old, and so the media breathlessly calls this arrested aging, but these are two quite different processes. The degeneration and loss of function in later aging is caused by accumulated damage that occurs as a side-effect of the normal operation of metabolism. The passage from childhood to adulthood is an evolved developmental program of growth and change. If that developmental program is broken, the individual will still age, will still accumulate cellular and tissue damage for so long as their metabolism is operating. It seems unlikely that there is anything of practical use for aging to be learned here, despite the hopes expressed by some of the people involved:

Epigenetic age analysis of children who seem to evade aging

We previously reported the unusual case of a teenage girl stricken with multifocal developmental dysfunctions whose physical development was dramatically delayed resulting in her appearing to be a toddler or at best a preschooler, even unto the occasion of her death at the age of 20 years. The pediatrician who cared for her from birth described his patient's strange affliction, that did not fit any disease category, as an "unknown syndrome" later to be called "syndrome X". As the result of her persistent "toddler-like" appearance, she received extensive notoriety from the media, and was featured as the "girl who doesn't age" in press articles and television broadcasts.

While most of the individual defects she experienced are not uncommon in many children, it was her retaining toddler-like features while aging from birth to young adulthood that made the case particularly unusual. Even children with growth retardation or failure to thrive exhibit maturation of facial and other physical/functional features with passage of time, indicating that their developmental program is still functional. In contrast, the peculiar trait of the first case suggested that her rate of aging was dramatically delayed or even arrested. If so, then perhaps an etiological understanding of her pathology might lead to novel treatments for age related diseases.

The objectives of this study were two-fold. The first was to determine if other such cases of syndrome X actually exist and thus might represent a novel syndrome. Then, because the case's appearance remained that of a toddler despite the passage of time, our second objective was to determine if there was any evidence that the arrested development in such children is linked to a slowing down of aging at the molecular level.

We identified five new cases whose clinical presentations were similar to the first case. Thus, while extremely rare, the first case described was not unique in the world. Furthermore, since such children require extensive medical care to survive, especially during the first years after birth, it may be that most succumb before ever being diagnosed. All of the identified subjects were female. It is not known whether this occurrence was due to chance alone or is a sex linked aspect of the putative syndrome.

To objectively measure the age of blood tissue from these subjects, we used a highly accurate biomarker of aging known as "epigenetic clock" based on DNA methylation levels. Our results demonstrate that despite the clinical appearance of delayed maturation in children afflicted with syndrome X, the epigenetic clock indicates that the rate of development in blood and perhaps other tissues is normal. Thus, while we cannot exclude tissue-specific ageing as causal in syndrome X, the current findings suggest that the observed delay in whole body development results from other, yet undiscovered factors. Future studies should assess whether other tissue types from these subjects (or their bodies as a whole) evade epigenetic aging.

I've made the case that the modern development of support for longevity science has arrived in waves of ten to fifteen years apiece, starting in the 1970s. Advocates of that era were very overconfident, not as integrated with the scientific community as today's crowd, and outright wrong about the prospects for the near future. Right in the long term, but not for the four decades between then and now. Those who founded the "anti-aging" marketplace built a pipeline in advance of any possible product, and then they sold out and filled that pipeline with junk: supplements, potions, and anything that sold. It is possible to be a success and yet still fail, and this is one of the great illustrations of that fact in our time.

Yet some of those folk kept the vision, and took the money they made selling out, and ran it back into trying to advance selected areas of research and development. In particular the people behind the Life Extension Foundation on the one hand have done a great deal to establish a damaging, ridiculous view of the efficacy of supplements in aging, helping to ensure that most people don't look beyond the supplement industry to think about medical research that might actually do something to meaningfully extend healthy life - something that cannot be achieved through supplements. On the other hand the LEF principals have helped build the cryonics industry, and funded legitimate stem cell, cancer, and SENS-like research projects over the decades. I have my own opinions on the final weighing of good and bad in all of this. It has taken a long time for the scientific community to wrest back the mantle of legitimacy for the study of extending human life spans, and much the past unwillingness of researchers in the field to engage with the public at all can be laid at the feet of the "anti-aging" marketplace, and the outright lies and fraud that continue to characterize its marketing.

Like many of the folk involved in the early life extension community, the principals at the Life Extension Foundation are characters. It is what you tend to find among those involved in carving out new fields of business and study: the meek and the commonplace need not apply. They seem to be engaged in a little amateur religious engineering at present, a venture I mentioned in a post last year, though at the time it hadn't clicked that these were the folk involved. It is a lengthy and interesting article on many levels; you should certainly read it all rather than walking away with the summaries in the opening section, as they are rather misleading:

In 2013, William Faloon and his longtime business partner, Saul Kent, bought, for $880,000, this building just north of downtown Hollywood that had formerly housed a Baptist congregation. They founded the Church of Perpetual Life, which hosts once-a-month meetings with a guest speaker and a social hour. Establishing the church is just the latest bold step in the duo's lifelong mission of trying to extend human lifespans. Faloon and Kent are controversial figures in a controversial field. The so-called "immortalist" movement encompasses strategies of "life extension," from taking vitamins to receiving organ transplants. It also includes cryonics, the idea that corpses can be cooled to extremely low temperatures and someday, somehow, be returned to life.

For their work, Faloon and Kent have been both hailed as visionaries and derided as snake-oil salesmen. They've been raided by the feds and thrown in jail for importing unapproved drugs. They've bankrolled a slew of curious cryonics projects, from the freezing of dogs to experiments in an underground house. Kent even had his own mother's head detached and cryopreserved, then had to fend off a murder investigation. Now, they're battling the IRS over the foundation's tax-exempt status.

None of this seems to bother Faloon much. A huge round of investment from the global 1 percent is now bringing immortalist ideas out of the realm of science fiction. Peter Thiel, founder of PayPal; Martine Rothblatt, founder of Sirius Radio; and Sergey Brin, CEO of Google, are just a few of the ultrarich who have recently begun to pour hundreds of millions of dollars into life-extension endeavors. Death, they are betting, is a scientific problem that can be solved. Says Faloon: "What I had hoped would happen in 1977 is finally happening in 2015."

Link: http://www.browardpalmbeach.com/news/bill-faloon-and-saul-kent-major-figures-in-cryonics-movement-start-a-church-in-hollywood-6969096

"Because I want to" is a perfectly fine and valid reason to live longer in good health, and the early stage development of rejuvenation biotechnology tentatively underway today is all about providing that choice where no viable options presently exist:

Not all of us want to live forever. However, few would pass at the chance of a guaranteed long and healthy life. Seeing our health decline as we grow older, and departing this earth often decades before our 100th birthday is a concept most of us reluctantly accept, but as medical, scientific and technological advances continue to make possible what we had thought impossible just years before, many now see this condition as no longer inevitable.

In recent years, a proliferation of individuals, groups, organisations, institutions and corporations have emerged with a stated mission to combat the effects of aging and prolong healthy lifespan. From the simple blogger, to the esteemed research institution, and on to the multi-billion dollar corporation, a huge and growing international network and community of like-minded people are now attempting to either promote the cause or directly find ways to extend healthy life. With the establishment of big-budget longevity research and development corporations such as the Google-backed Calico and J. Craig Venter co-founded Human Longevity Inc., as well as media focus on high-profile investors such as PayPal founder Peter Thiel, the subject of human longevity is finally moving from the radical or even taboo to become both a key point of discussion and multi billion dollar industry.

But why extend life? Firstly, dying of 'old-age' is in itself a myth. Instead 'damage' to our bodies which accumulates naturally throughout our lifetime leaves us more susceptible to numerous medical conditions such as cancer, heart and lung disease and brain dysfunctions such as Parkinson's and Alzheimer's as we get older. It is the increased inability of the aged body to combat these diseases which results in death, not age itself. If ways can be found to minimise this damage, repair, and negate the effects it has upon us later in life, then there is no reason why the years in which we enjoy a fully mobile healthy existence both physically and mentally cannot be prolonged in a significant way, and extended beyond what is currently possible in even the most long-lived individuals. Man-made advances in science, medicine and technology have already resulted in us living far longer than our ancestors, so why not find ways that we can stay healthy for longer too? The effect this could have upon lifespan, we don't know, but life extension isn't just about living longer. It is about finding ways to prolong the time we spend in peak condition.

Link: http://lifemag.org/article/why-extend-life

The SENS Research Foundation, alongside its parent organization the Methuselah Foundation, is one of the most important scientific non-profits in the world today. These organizations are undertaking seed research, engaging in persistent advocacy, and organizing conferences to steer the scientific and funding communities onto the best paths to produce the toolkit of therapies and biotechnologies needed to achieve human rejuvenation. This means building ways to repair the catalog of cell and tissue damage that causes age-related fraity and disease, and thus reverse its progression. The goal is old age without pain, without suffering, without any loss of health and vigor, and given the right strategies in research and development, this is a practical goal for the decades ahead.

The SENS Research Foundation has a tiny budget for an organization that seeks to profoundly change the world for the better: entirely funded by philanthropic donations at $5 million each year. It is never the intent that the SRF staff and associated researchers do everything themselves, however. The point of the exercise is to steer other funds and other scientific groups towards the best possible lines of research by demonstrating their worth, and by making sure that everyone in the scientific community knows about past demonstrations carried out elsewhere. Does this really work at this sort of funding level, however? The answer is a resounding hell yes it works, even if more is always better.

If you have been paying attention for the past decade you'll notice that these days there are several lines of SENS research that are spreading out and being picked up by people with deeper pockets. Senescent cell clearance has had its arrival year this year, with a great technology demonstration of improved healthspan in aging mice. Similar the targeting of telomere extension as the common mechanism in all cancer is a SENS approach that now has some people in the mainstream research community working on a variety of initiatives, while the SENS Research Foundation in-house efforts are respectfully covered by the popular science media.

Ten years ago, the people who publicly proposed exactly this research were mocked, and all too many scientists avoided talking about extending healthy human life by treating the causes of aging. Now it is a very different story. All those community fundraisers in the past, all of the advocacy, all of the grassroots efforts? They pay off. Not immediately, because it takes years to make things happen. But we can clearly see the results arriving now. There are yet more areas of SENS research that need to have their day in the sun, however, which is why we must double down and keep on trucking. We're starting to win the game in earnest, the wheel is moving, the avalanche started, so why stop here?

The SENS Research Foundation in fact probably gets more media attention than your average non-profit of its size, and justifiably so. Nowhere near enough media attention, I'd say. Research into repairing the causes of aging needs to be right up there in the public conversation alongside cancer research, and the funding should be much the same. That is a thing to aim for, and the sooner we get there the better the prospects for a future that doesn't involve sickness and decline. Here are a couple of recent items covering the SENS Research Foundation and its staff:

New innovation to extend life expectancy

Tucked away in a small office in the heart of Silicon Valley, the SENS research foundation is engaged in the cutting-edge work of rejuvenation biotechnology. They experiment with preservation of the cell and, more specifically, the powerhouse of the cell: the mitochondria.

With donations primarily from philanthropists, SENS operates on a US$5million annual budget that founders consider a drop in the bucket compared to what is spent on healthcare. SENS's approach is still a long away from being used on people, as it would likely need testing on animals first before being incorporated in human gene therapy, a technique also still under study.

Front and Center: Singer, Composer, Pilot, Global Outreach Coordinator at SENS Research Foundation, Maria Entraigues-Abramson

WiMN: You're currently the Global Outreach Coordinator for SENS Research Foundation. How has your experience as a singer and composer helped you with this role?

MEA: As you can probably tell I can't stay on just one thing. I've always had this unstoppable curiosity since I was a little girl, and science has been one of my other big passions. SENS Research Foundation is a non-profit organization located in the Bay Area, working to develop new therapies to prevent, reverse and eradicate the diseases of aging. As we age we accumulate damage at a cellular and molecular level, that happens since we are born.

This damage or "junk" as we call it, doesn't bother us much until we start getting older. When the amount of waste crosses a certain threshold it starts affecting the functions in our body and we get sick. If we live long enough, in the way medicine is today, we will get at least one age related disease (cancer, Alzheimer's, cardiovascular disease, Parkinson's, etc) if not several, and if we don't die of something else before, this is what will eventually kill us.

At SRF we have a roadmap to get aging under medical control. These strategies (Strategies Engineered for Negligible Senescence) were designed by biogerontologist Dr. Aubrey de Grey, a very prominent scientist from Cambridge, U.K., who co-founded the organization and is our Chief Science Officer. He wrote the book Ending Aging where he explains the seven types of damage that make us age and how we can tackle them using regenerative medicine. This is what we work on.

My work as the Global Outreach Coordinator is mainly development and fund raising. I focus on creating new relationships, bringing high net worth Individuals onboard. I do celebrity outreach, organize events, and anything that will help create awareness and raise funds to push the research and the development of treatments forward. These cures will happen, it is just a matter of time, and the more funding we get the faster it will happen. The fact that I've been in the music/entertainment business for so long helped me build a huge network of people and this is how I can do my job doing outreach for the organization, it is all about making connections and expanding our network.

Researchers here demonstrate the utility of incorporating a hydrogel into stem cell therapies, where it can improve survival of the transplanted cells and the outcome for the patient:

Stem cells hold great therapeutic promise because of their ability to turn into any cell type in the body, including their potential to generate replacement tissues and organs. While scientists are adept at growing stem cells in a lab dish, once these cells are on their own - transplanted into a desired spot in the body - they have trouble thriving. The new environment is complex and poorly understood, and implanted stem cells often die or don't integrate properly into the surrounding tissue. Researchers created a hydrogel several years ago as a kind of a bubble wrap to hold cells together during transport and delivery into a transplant site. "This study goes one step further, showing that the hydrogels do more than just hold stem cells together; they directly promote stem cell survival and integration. This brings stem-cell based therapy closer to reality."

In addition to examining how the stem cells benefit from life in hydrogels, the researchers also showed that these new cells could help restore function that was lost due to damage or disease. The team injecting hydrogel-encapsulated photoreceptors, grown from stem cells, into the eyes of blind mice. Photoreceptors are the light sensing cells responsible for vision in the eye. With increased cell survival and integration in the stem cells, they were able to partially restore vision. "After cell transplantation, our measurements showed that mice with previously no visual function regained approximately 15% of their pupillary response. Their eyes are beginning to detect light and respond appropriately."

In another part of the study, researchers injected the stem cells into the brains of mice who had recently suffered strokes. "After transplantation, within weeks we started seeing improvements in the mice's motor coordination." The team now wants to carry out similar experiments in larger animals, such as rats, who have larger brains that are better suited for behavioral tests, to further investigate how stem cell transplants can help heal a stroke injury.

Link: http://news.engineering.utoronto.ca/hydrogels-boost-ability-of-stem-cells-to-restore-eyesight-and-heal-brains/

Approaches towards targeting cancer are becoming ever more sophisticated, even as the same basic goal remains unchanged: deliver far lower doses of cell-killing treatments to a far smaller area, even to individual cancer cells where possible, reducing side-effects and damage to everything except the targeted tumor or cancer cells. There are many possible ways to achieve this end, and this one has many potential applications beyond merely cancer treatment:

Attacking the perennial problem of systemic toxicity from typical chemotherapy treatments, researchers have engineered therapeutic cells encapsulated in nanoporous capsules to secrete antitumor molecules from within the tumor. "We have engineered cells that locally convert a nontoxic substance into an antitumor agent. We can encapsulate cells in nanoporous capsules, which ensures the cells are localized and immunoisolated. This immunoisolated micro-factory can remain in the tumor, providing a permanent and renewable source of therapeutic molecules for long-term cancer management."

Engineered bacterial cells that are designed to express therapeutic enzymes under the transcriptional control of remotely inducible promoters can mediate the de novo conversion of nontoxic prodrugs in their cytotoxic forms. In situ cellular expression of enzymes provides increased stability and control of enzyme activity as compared to isolated enzymes. The team engineered Escherichia coli (E. coli), which was designed to express cytosine deaminase at elevated temperatures under the transcriptional control of a thermo-regulatory promoter cassette. This constituted the thermal switch to trigger enzyme synthesis. They subsequently co-encapsulated the cells with magnetic iron oxide in immunoprotective alginate microcapsules and then remotely triggered cytosine deaminase expression by alternating magnetic field-induced hyperthermia.

The goal of localizing therapy to avoid systemic toxicity from chemotherapy is the impetus for the vision to ultimately encapsulate a library of therapeutic cells that will take cues from their microenvironment and secrete appropriate antitumor molecules. Looking forward, the work will focus on using these microencapsulated cells to stimulate the immune system to act against tumors, as well as activating drug synthesis.

Link: http://cancer.dartmouth.edu/about_us/newsdetail/73456/

Cytomegalovirus, CMV, is a prime suspect in one of the characteristic malfunctions seen in the aging human adaptive immune system. CMV is a very prevalent form of herpesvirus, and something like 90% of individuals test positive for exposure by the time old age rolls around. Most people have no noticeable symptoms of infection, and CMV is usually only a topic in clinical practice when it comes to immune compromised patients or transmission to unborn children, both situations in which infections largely harmless to everyone else can become a threat. While it is indeed largely harmless in the short term, like all herpesviruses CMV lingers latent in the body to emerge over and again to challenge the immune system.

The scenario suspected of CMV is that while its latent infection goes unnoticed in the vast majority of people, every time the virus emerges from hiding ever more T cells specialize as memory T cells that identify CMV. The immune system in adults has a low pace of replacement for T cells, and is effectively running in a capacity system: there are only so many cells to go around at any one time, and over the years ever more of that limited resource is devoted to CMV rather than to facing down new threats. At present this is a compelling hypothesis in the research community rather than a proven absolute. What is definitively observed in old people is an expansion of less useful T cells such as memory cells, a dysregulation of the immune system that occurs at the expensive of naive T cells and other types needed for a robust immune response. The immune system is complex and far from fully understood, and so there are competing explanations for this observation; pointing to the actions of CMV is one of the better supported hypotheses.

What to do about all of this? The engineering approach, which already has some backing from past animal studies, is to focus on selectively destroying the unwanted immune cells. They have a fairly distinctive surface chemistry, and the cancer research community is pouring a great deal of time and effort into the development of ways to safely and selectively destroy cells in living tissue based on these and other identifiable differences. If the misconfigured immune cells are cleared out, the hope is that they will be replaced with fresh copies that are not burdened by a lifetime of responding to CMV, and the immune system will be brought back into balance. The fastest way to quantify the effectiveness of this approach is to try it, given the technologies available today and the pace of discovery. Indeed, clearance of innate immune cells had this beneficial outcome in animal studies. Sadly there is all too little work on this front at the present time, as is the case for many of the more direct approaches to repairing the causes of age-related dysfunction and frailty.

Here is an interesting open access paper on a primate study of CMV, comparing two groups with and without exposure to the virus, that adds more supporting evidence for its role in immune system dysfunction in aging. The particular groups used perhaps offer a platform for further and more incisive investigations in the future:

The interplay between immune maturation, age, chronic viral infection and environment

The worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence. Here, we propose that rhesus macaques could serve as a relevant model to define the impact of chronic viral infections on host immunity in the aging host. We evaluated whether chronic rhesus CMV (RhCMV) infection, similar to HCMV infection in humans, would modulate normal immunological changes in the aging individual by taking advantage of the unique resource of rhesus macaques that were bred and raised to be Specific Pathogen Free (SPF-2) for distinct viruses.

Our results demonstrate that normal age-related immunological changes in frequencies, activation, maturation, and function of peripheral blood cell lymphocytes in humans occur in a similar manner over the lifespan of rhesus macaques. The comparative analysis of age-matched SPF-2 and non-SPF macaques that were housed under identical conditions revealed distinct differences in certain immune parameters suggesting that chronic pathogen exposure modulated host immune responses. All non-SPF macaques were infected with RhCMV, suggesting that chronic RhCMV infection was a major contributor to altered immune function in non-SPF macaques, although a causative relationship was not established and outside the scope of these studies. Further, we showed that immunological differences between SPF-2 and non-SPF macaques were already apparent in adolescent macaques, potentially predisposing RhCMV-infected animals to age-related pathologies.

Our data validate rhesus macaques as a relevant animal model to study how chronic viral infections modulate host immunity and impact immunosenescence. Comparative studies in SPF-2 and non-SPF macaques could identify important mechanisms associated with inflammaging and thereby lead to new therapies promoting healthy aging in humans.

Mitochondria are the power plants of the cell, every cell equipped with a herd of hundreds of them, constantly recycled by cell quality control mechanisms and the numbers kept up by division like bacteria. Damage to mitochondria is thought to be important in aging, specifically damage to the DNA that all mitochondria carry. Some forms of mitochondrial DNA damage can lead to dysfunctional mitochondria that evade cellular quality control mechanisms even though broken, and thus proliferate to take over their cell, causing it to malfunction and export damaging reactive molecules into surrounding tissues.

These researchers have a different take on this contribution to the aging process, theorizing in an open access paper that the RNA produced from damaged mitochondrial DNA is also a consideration:

Accumulations of mitochondrial DNA (mtDNA) mutations associated with aging are evident in multiple human tissues. The role of mtDNA mutations can be observed in an aging animal model such as homozygous knock-in PolgA mice, which have a large colonial expansion of mtDNA mutations. They develop reduced lifespan and premature onset of age-related phenotypes, that are also observed in clinical practice like mitochondrial aging acceleration with anti-retroviral therapy through clonal expansion of mtDNA mutations.

These clonally expanded mtDNA mutations maintain transcription ability which could result in an accumulation of abnormal mitochondrial RNA (mtRNA) in the affected cells. Compensation-effect doctrine states that accumulated mtDNA mutations in the cell must reach a set threshold before they have a negative effect on cell function due to compensation effects from normal cellular mtDNA. In contrast to this theory, we suggest that an accumulation of aberrant mtRNA transcribed from mtDNA mutations negatively influences cellular function through complex internal and external mitochondrial pathways, and might be an important cause of aging and aging-associated diseases.

Link: http://dx.doi.org/10.1016/j.mehy.2015.04.022

The next few decades will see competition between regenerative medicine and prosthetic design in the construction of replacement organs. At some point in the future the two will merge, most likely after a molecular nanotechnology industry emerges and becomes capable of manufacturing designs as complex and reliable as evolved cell biology. There are attempts today to build bioartificial organ substitutes that combine tissue and machinery, but designing artificial organs remains an undertaking still in its infancy, beset with challenges:

One of the biggest problems with ventricular assist devices (VADs), as well as with existing artificial hearts, is that they can damage the blood. Through shear stress, delicate platelets - whose function is to stop bleeding in normal situations - can become "activated," causing thrombosis or clots, which can lead to stroke or heart attack. It's the reason why patients require comprehensive anti-coagulation medication, which can have problematic side effects as well. Red blood cells can also be damaged by the high shear stresses caused by pumps and leach hemoglobin, causing more problems.

So how should an artificial heart pump blood? Should it run continuously at a steady rate, or pulsate like a real heart? Should it be made of synthetics, organic materials, or a combination of both? Currently most VADs rely on centrifugal or axial flow pumps to circulate blood via a rotary impeller, much like a sump pump moves water out of a flooded basement. These pumps rotate at high speeds - 5,000 to 10,000 rpms - in order to circulate in a minute the approximately 5 liters of blood in a human body. But all that pressure can cause problems. "It's like the force that's coming out of a water hose, and these poor little, innocent platelets are very sensitive to turbulence."

Researchers came up with the idea of using a completely different kind of pump, one that uses a peristaltic pumping mechanism - a far more gentle way of moving fluid. Peristaltic pumps rely on a symmetrical contraction and relaxation motion to generate a wave down a tube. It's basically how your gastrointestinal system transports food through the intestines. Peristaltic pumps are already used in heart/lung blood machines to circulate blood in and out of a patient during open-heart surgeries, but they have never been used in VADs or in artificial hearts.

Another challenge for researchers is trying to map the brain-heart connection. When you're lying down and want to get up, your brain tells the heart to beat faster, to pump more blood. Your body simply reacts. But how will a person's nervous system involuntarily control an artificial heart? "The classic example is a baseball player at the plate who isn't really doing anything. But as soon as the pitcher throws the ball, a dozen different things occur automatically. Blood flow increases, there's a rush of adrenaline. It doesn't look like he's doing anything, but the body reacts to that stimulus in a way that's profoundly different than just sitting there. The mechanical heart wouldn't care that here comes a 90 mph pitch. But we want it to care. We want it to know the difference." If an artificial heart contained enough organic material, could the body's neurological pathways reconnect with it?

Link: http://hub.jhu.edu/gazette/2015/may-june/focus-can-we-build-a-better-heart

Heterochronic parabiosis is one of the research success stories of recent years. By linking the circulatory systems of an old and a young individual, usually laboratory mice, researchers have learned that levels of signal proteins circulating in blood and tissue change with age, and that these signals are the proximate cause of a great deal of the characteristic decline in stem cell activity that occurs with aging. The full story likely involves reactions to low-level cell and tissue structure damage that in turn change the balance of proteins generated and circulated, and stem cells react to this information by damping down their activity.

The consensus view in the research community is that this and other similar changes over the course of aging exist because they reduce the risk of cancer. Cancer is a game of chance, awaiting the right combination of mutations and cell damage. The more that damaged cells undertake activity such as replication then the higher the odds of spawning the seeds of a tumor. But if cells, and stem cells in particular, are less active then tissues and organs malfunction and weaken. Life span then is an evolved balance between death by cancer on the one hand and death through loss of tissue maintenance on the other, with natural selection favoring a balance that achieves a life span that produces success for the species in its niche.

The stem cell and parabiosis fields of research have produced a range of ways to spur greater activity in old and damaged cell populations. Many forms of simple stem cell transplant appear to work because the transplanted cells deliver signals that instruct native cells to be more active, for example. Interestingly, these lines of work have largely shown much less of a cancer risk in the laboratory and the clinic than was expected at the outset. It may well be that the evolved balance in mammals can be favorably adjusted towards greater stem cell maintenance of tissues, and extended healthy life as a response, but it is still a little early to be more than modestly optimistic on this front, I think. A way to activate dormant stem cells doesn't do much at all to revert the levels of cellular and molecular damage that cause aging. It only partially solves one problem, the diminished numbers in useful and necessary cell populations. Beyond that there are metabolic wastes inside and outside cells, lingering senescent cells, high levels of stochastic DNA damage, cells taken over by malfunctioning mitochondria, and more. Aging is a lot more than just stem cell dysfunction.

There was considerable excitement over the last drug target to emerge from parabiosis research, GDF-11. Increased levels of GDF-11 in the bloodstream put stem cells back to work in old mice and produced meaningful benefits in measures of health. This latest research is similar in nature, but involves a very different mechanism, possibly connected to regulation of chronic inflammation and its effects on stem cell activity:

Drug perks up old muscles and aging brains

Aging is ascribed, in part, to the failure of adult stem cells to generate replacements for damaged cells and thus repair the body's tissues. Researchers have shown that this decreased stem cell activity is largely a result of inhibitory chemicals in the environment around the stem cell, some of them dumped there by the immune system as a result of chronic, low-level inflammation that is also a hallmark of aging.

In 2005, researchers infused old mice with blood from young mice - a process called parabiosis - reinvigorating stem cells in the muscle, liver and brain/hippocampus and showing that the chemicals in young blood can actually rejuvenate the chemical environment of aging stem cells. Last year, doctors began a small trial to determine whether blood plasma from young people can help reverse brain damage in elderly Alzheimer's patients. Such therapies are impractical if not dangerous, however, so researchers are trying to track down the specific chemicals that can be used safely and sustainably for maintaining the youthful environment for stem cells in many organs. One key chemical target for the multi-tissue rejuvenation is TGF-beta1, which tends to increase with age in all tissues of the body and which depresses stem cell activity when present at high levels.

Researchers showed that in old mice, the hippocampus has increased levels of TGF-beta1 similar to the levels in the bloodstream and other old tissue. Using a viral vector developed for gene therapy, the team inserted genetic blockers into the brains of old mice to knock down TGF-beta1 activity, and found that hippocampal stem cells began to act more youthful, generating new nerve cells. The team then injected into the blood a chemical known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta1. This small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent, successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever. "The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like. Dosage is going to be the key to rejuvenating the stem cell environment."

Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations.

At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.

The present swamp of slow and expensive progress in cancer research is a swamp because every type of cancer is biologically very different, and most research programs are thus applicably only to a narrow slice of the exceedingly broad spectrum of cancers. Even there it is frequently the case that individual tumors are so highly varied that a vulnerability in one individual's cancer of a specific type is not present in another. There are better ways forward, however: progress in cancer research can be greatly accelerated by finding and focusing on common mechanisms shared by many different cancers. This has long been the SENS approach to cancer, to strike at the one known common mechanism shared by all cancers, which is to say their need to extend telomeres. Telomeres shorten with each cell division, and when too short a cell will destroy itself. This limits the number of times any ordinary cell in the body can divide, and cancers must thus break this limiting function in order to retain their uncontrolled growth.

A decade ago it was sadly the case that, as for any bold new plan, the SENS research program as an approach to medicine to treat degenerative aging and its consequences - such as cancer - was mocked. Today, however, numerous research groups are attempting to disrupt telomere extension in cancer. Times have changed, and the world is finally catching up to the perspective of earlier visionaries in aging research. Present work on disruption of telomere lengthening in the broader scientific community is largely aimed at blocking the activity of telomerase, while the SENS Research Foundation cancer program nowadays focuses on the less well researched alternative lengthening of telomere mechanisms.

Here researchers are taking an entirely different approach by attacking the structure of telomeres directly, rather than interfering in lengthening mechanisms, thus stripping telomeres from chromosomes in target cells:

Researchers have discovered a new strategy to fight cancer, which is very different from those described to date. Their work shows for the first time that telomeres - the structures protecting the ends of the chromosomes - may represent an effective anti-cancer target: by blocking the TRF1 gene, which is essential for the telomeres, they have shown dramatic improvements in mice with lung cancer. "Telomere uncapping is emerging as a potential mechanism to develop new therapeutic targets for lung cancer."

Every time a cell divides, it must duplicate its genetic material, the DNA, which is packed inside the chromosomes. However, given how the mechanism of DNA replication works, the end of each chromosome cannot be replicated completely, and, as a result, telomeres shorten with each cell division. Excessively short telomeres are toxic to cells, which stop replicating, and eventually, the cells are eliminated by senescence or apoptosis. This phenomenon has been known for decades, as well as the fact that it usually does not occur in tumour cells. Cancer cells proliferate without any apparent limits, and therefore, they are constantly dividing, but their telomeres do not gradually become shorter; the key behind this mechanism is that the telomerase enzyme in cancer cells remains active, while in most healthy cells telomerase is turned off.

Telomeres are made up of repeating patterns of DNA sequences that are repeated hundreds of times - this is the structure that shortens with each cellular division. Telomere DNA is bound by a six-protein complex, called shelterin, which forms a protective covering. The research team strategy consisted of blocking one of the shelterins, namely TRF1, so that that the telomere shield was destroyed. The idea of targeting one of the shelterins has not been tried so far, due to the fear of encountering many toxic effects caused by acting on these proteins that are present in both healthy and tumour cells.

"Nobody had explored the idea of using one of the shelterins as an anti-cancer target. It is difficult to find drugs that interfere with protein binding to DNA, and the possibility exists that drugs targeting telomere caps could be very toxic. For these reasons, no one had explored this option before, although it makes a lot of sense. TRF1 removal induces an acute telomere uncapping, which results in cellular senescence or cell death. We have seen that this strategy kills cancer cells efficiently, stops tumour growth and has bearable toxic effects." Having established the effectiveness and low toxicity of the new target, the researchers searched for chemical compounds that could have activity against TRF1. Two types of compounds have been found. "We are now looking for partners in the pharmaceutical industry to bring this research into more advanced stages of drug development."

Link: http://www.eurekalert.org/pub_releases/2015-05/cndi-csa051115.php

Many stem cell therapies seem to work via cell signaling rather than any other activity of the transplanted cells, the signals spurring native cells to get back to work and regenerate tissues. Knowing this, the logical end goal of research is then a class of therapy that delivers the signal chemicals rather than cells. Progress on this front is really only limited by the present comparatively poor understanding of just which signals are important in various different circumstances:

Scientists have discovered a way to regrow bone tissue using the protein signals produced by stem cells. The new study is the first to extract the necessary bone-producing growth factors from stem cells and to show that these proteins are sufficient to create new bone. Instead of using stem cells themselves, the scientists extracted the proteins that the cells secrete - such as bone morphogenetic protein (BMP) - in order to harness their regenerative power. To do so, the researchers first treated stem cells with a chemical that helped coax them into early bone cells. Next, they mined the essential factors produced by the cells that send the signal to regenerate new tissue. Finally, the researchers delivered these proteins into mouse muscle tissue to facilitate new bone growth.

The stem cell-based approach was as effective as the current standard treatment in terms of the amount of bone created. This current standard method involves grinding up old bones in order to extract the proteins and growth factors needed to stimulate new bone growth - a substance dubbed demineralized bone matrix (DBM). However, this approach has significant restrictions as it relies on bones taken from cadavers, which can be highly variable in terms of tissue quality and how much of the necessary signals they still produce. Moreover, as is the problem in organ donation, cadaver tissue is not always available. "These limitations motivate the need for more consistent and reproducible source material for tissue regeneration. As a renewable resource that is both scalable and consistent in manufacturing, pluripotent stem cells are an ideal solution."

Link: http://gladstoneinstitutes.org/pressrelease/2015-05-11/scientists-regenerate-bone-tissue-using-only-proteins-secreted-by-stem-cells

Salamander regeneration is becoming well studied. Researchers are mining the biochemistry of this and other proficient regenerator species such as zebrafish, as they would like to port over the ability to regrow limbs and internal organs into humans via the application of suitably designed medical biotechnology. At present it is an open question as to whether this a practical goal for the near future. While the past decade of investigation has uncovered a great deal of interesting new information on exactly how organ regeneration progresses in these species, it hasn't pulled out any one obvious manipulation that could be attempted in human biochemistry. So at this point making humans regrow lost limbs and organs in the same way that salamanders are capable of might prove be anything in between the extremes of (a) an enormously complicated reforging of our fundamental biochemistry better suited for the 2050s than the 2020s, and (b) something strikingly obvious in hindsight that could be implemented today were the details made clear. We just don't know yet.

On a completely separate topic, interest is picking up in senescent cells as a target for the treatment of aging. A demonstration of improved healthspan in mice through partial clearance of senescent cells was made public earlier this year, and that was the culmination of several years of murmurings following earlier, less compelling technology demonstrations. Several research teams are working on different methods of achieving the same end, at various very early stages on the road to readiness for clinical trials. Senescent cells contribute to aging in near every tissue: they accumulate over time in response to cell damage or a potentially damaging tissue environment, and not enough of them are destroyed by their own programmed cell death mechanisms or the watchful eye of the immune system, ever alert for errant cells that should be removed from the picture. Every senescent cell emits a cocktail of signal molecules that corrodes the nearby extracellular matrix and changes the behavior of surrounding cells for the worse. Enough of that and organ function declines into disease states.

Give these two contexts, this recent open access research is rather intriguing. It seems that salamander immune cells are exceedingly effective at destroying senescent cells during their regenerative process, and indeed at other times as well - which adds another mechanism that would be nice to port to humans if at all possible. Note that the full paper is PDF format only at this point, and so you'll have to click through to download and read it.

Recurrent turnover of senescent cells during regeneration of a complex structure

Cellular senescence has been recently linked to the promotion of age-related pathologies, including a decline in regenerative capacity. While such capacity deteriorates with age in mammals, it remains intact in species such as salamanders, which have an extensive repertoire of regeneration and can undergo multiple episodes through their lifespan. Here we show that, surprisingly, there is a significant induction of cellular senescence during salamander limb regeneration, but that rapid and effective mechanisms of senescent cell clearance operate in normal and regenerating tissues. Furthermore, the number of senescent cells does not increase upon repetitive amputation or ageing, in contrast to mammals.

It is clear that salamanders possess a rapid and efficient mechanism to recognise and clear senescent cells that either arise endogenously, or are introduced from culture. Our study demonstrates that a robust macrophage-dependent surveillance mechanism operates in normal and regenerating tissues of adult salamanders, and this allows them to circumvent the negative effects associated with the long-term accumulation of senescent cells, such as the disruption of tissue structure and function. These surveillance mechanisms are particularly significant for limb regeneration because there is a notable induction of cellular senescence during this process. Consistent with this, recent reports show that systemic macrophage depletion during salamander limb regeneration leads to defects in this process.

We propose that effective immunosurveillance of senescent cells in salamanders supports their ability to undergo regeneration throughout their lifespan. It has recently been suggested that targeting senescent cells could lead to therapeutic strategies for age-related pathologies. Here, we identify an animal with an efficient mechanism for surveillance of senescent cells operating through adulthood. Analysis of this mechanism could lead to the identification of novel therapeutic targets for the amelioration of age-related disorders and extension of healthspan.

There is a further interesting twist here. The occurrence of cellular senescence in aging may well be an evolutionary adaptation of its role in embryonic development, where it is thought to act as a guide in the development of tissue shape, such as at the tips of limbs and fingers. In this light, the greater presence of senescent cells during salamander regeneration might not be all that surprising: at the level of cellular organization regrowth of a limb acts in many ways like the embryonic development of that same limb. So is improved immune surveillance of senescent cells in salamander regeneration just the same thing that already happens in mammals during their embryonic development? Or is it something quite different, as indicated by the fact that it operates all the time and across a lifespan? These are not questions with definitive answers, and so, as for regeneration itself, further research is needed to understand whether or not greater immune clearance of senescent cells can be brought from salamander to human as a practical concern.

Vascular stiffening is a major cause of cardiovascular aging. It alone is enough to explain the age-related onset of hypertension, for example, which in turn deforms blood vessels and the heart, and causes ongoing harm to the brain where small blood vessels fail under stress, among other issues. Much of the cause of loss of elasticity in blood vessels is thought to be caused by cross-linking and calcification in the extracellular matrix, processes that occur as a side-effect of the normal operation of metabolism, and which could be reversed with suitably designed drugs. Unfortunately there is still comparatively little research focused on these targets, certainly nowhere near as much as is merited by the consequences of these contributing causes of degenerative aging.

Here, researchers identify another potential causative agent in the stiffening of blood vessels, in changing behaviors and characteristics of the smooth muscle cells that surround blood vessels. Is this a primary cause or a reaction to primary causes, however? More research is needed on that topic, as is often the case:

Arterial and vascular stiffness occurs through the normal process of biological aging and is associated with an increased risk of heart attacks and strokes. As we age, the aorta, which normally acts as a shock absorber dampening the pulse associated with each heartbeat, tightens and becomes rigid, causing a host of problems including high blood pressure, increased risk of adverse cardiovascular events and even death. In the United States, the risk of developing hypertension due to aging is greater than 90 percent in both men and women. Recent studies have identified several mechanisms for arterial stiffness in humans. Research has focused on the structural matrix proteins, or non-living components that compose the outer walls of blood vessels, as well as endothelial cells which line the inner portion of the vascular walls.

Researchers have focused on a new potential source - smooth muscle cells that are a major component of the "middle" of the blood vessel wall. The team isolated aortic cells from normal and hypertensive rat models in both young and aged animals. Then, using atomic force microscopy, an advanced microscope that incorporates a tiny probe that can interact with single cells and molecules, the team measured the compression force of the needle against the specimen and how the tip adhered to or "stuck" to smooth muscle cells.

"We found that hypertension increased both vascular smooth cell stiffness and adhesion or stickiness, and that these changes were augmented by aging. Our results are adding to our understanding and taking studies in a different direction. Although all cells are contributing to arterial stiffness, it's important to identify the order in which they're adding to the problem. Identifying smooth muscle cells as a contributor can help identify possible preventatives and potential drugs to counteract and reverse the disease and keep vessels healthier as we age."

Link: http://munews.missouri.edu/news-releases/2015/0511-new-cause-discovered-for-arterial-stiffness-a-contributor-to-cardiovascular-disease/

The small cryonics industry provides a vital service that all too few people avail themselves of. Low temperature preservation after death via vitrification ensures a chance at life again in the future. Provided that the fine structure of the brain is maintained, a preserved individual can wait indefinitely for the arrival of biotechnologies and nanotechnologies needed for restoration to life: a new body, cellular and structural repair of the brain, undoing all of the chemistry introduced in the preservation process, and so forth. It is an unknown chance, but nonetheless the only option going for those who will not live long enough to benefit from the rejuvenation and radical life extension that lies ahead as a result of progress in the science of aging. Here is a lengthy medical insider's view of the industry and its procedures, and the challenges inherent in public attitudes towards cryonics:

For me, cryopreservation was an obvious mechanical problem. You've got molecules; why not lock them in place so that somebody can fix them later? All these things happening in our cells are just mechanical processes - they are just little machines, basically - and if you can stop them before they start to disintegrate, that seems like a good thing. Before that I was a physician, but I haven't practiced for about five years now. I still have my license. My participation in the cryonics field happened very gradually. There's a lot of different things that need to be done. It takes a lot of people. I am the leader and do the surgical procedures as well. I keep the instruments organized and I write out the procedures.

Each case can be very different. I'll pick a generic case. We might get notified that a member of ours is sick, maybe a few weeks from dying, and maybe they're located in a nearby state so we have to mobilize and get our equipment nearby to be ready for when they are pronounced legally dead. Let's say they're in a hospice situation in some sort of a care facility - that would be better than a hospital because in a hospital they don't like other people coming in with their own equipment. If we see that they're getting closer to death, like a day or two out, we might try to get the equipment even closer to their bed. When they finally stop breathing, the heart stops, and the doctor pronounces them dead, then we take over.

We are trying to preserve all the intricate branches, about 2000, on each neuron, as well as the specific shapes of each synapse. If we cool them, it lengthens the amount of time before the neurons actually die. So we try to keep these cells alive as long as we possibly can. We put the person in an ice-bath - it's kind of like a stretcher with walls on it that contains ice water. That's the fastest we can cool externally. We start cooling, we start moving them out of the facility, we try to give medications that will stop the blood from clotting and will help slow down the metabolism further. An important one would be an antibiotic: we don't want bacteria to grow while we're doing this. Another important one would be to prevent blood clotting, and we want to constrict the blood vessels on the extremities to concentrate the blood flow to the core.

We move them out of there to a different facility where we can perform surgical procedures.We would prefer to start surgical procedures immediately. If the setting allows it, that's actually our standard protocol. We drain the blood out and replace it gradually with a cryoprotectant, like an antifreeze. That takes hours: to do the cooling and to pump those other chemicals in. Then we start cooling sub-zero, taking them down below the freezing point of water. If we do it right, we won't get ice crystals in the brain. That's called vitrification. It's never 100% perfect. There's always going to be ice crystals somewhere so its a matter of degrees; it's a matter of how much we can prevent that. There are different ways of sub-zero cooling: we can use dry ice, we can use nitrogen gas, circulate cold air over them. At some point, we remove the head usually because we don't need the rest of the body. That's not where the brain is. Sometimes we remove the brain also before we start the sub-zero cooling so it kind of depends on the patient. Then we take them down to -196 Celsius and immerse them in liquid nitrogen, and there they'll sit.

Link: http://www.hopesandfears.com/hopes/city/what_do_you_do/213599-cryonics-interview

Stem cell populations in the body are responsible for tissue maintenance, at the very least by keeping up a steady supply of new somatic cells to replace those that have reached their replication limits, but also via a range of other less well cataloged signaling processes. The latter category has become much more interesting to clinical researchers since the advent of the present generation of stem cell therapies, many of which produce benefits despite the fact that the transplanted stem cells don't actually contribute any meaningful number of daughter cells to the recipient. The boost to regeneration is all in the signals exchanged between cells, the levels of various proteins in the tissue environment.

Stem cell activity declines with advancing age, and the progressive failure tissue maintenance provides a strong contribution to the onset of dysfunction and age-related disease. At present this phenomenon is most closely studied in muscle tissue and the supporting population of stem cells known as satellite cells. This is where researchers have the most experience and greatest body of knowledge, and it is where most of the really interesting discoveries in stem cell aging have occurred in recent years. The picture building here may or may not also be the case in other tissues, but it is encouraging nonetheless. Insofar as muscle goes, the failure of stem cell activity consists of growing quiescence more than a depletion of numbers or some form of damage inherent to stem cells. This is a reaction to a changing balance of signals in the tissue environment, which in turn is a consequence of growing levels of the low-level cellular and tissue damage that is at root the cause of aging. Since signals are the proximate cause, changing the signals - and cell behavior - is well within the reach of present day biotechnology. The hardest part of this process is finding the relevant signals amid the vast complexity of an aging biochemistry.

So in recent years, researchers have focused on FGF-2, and GDF-11, and a range of other possible candidate signal molecules associated with various fundamental cell behaviors. The degree to which stem cell activity can be restored without immediate signs of harm due to damage is very encouraging, albeit surprising. The caution here has all along been the threat of cancer: the predominant hypothesis regarding the existence of stem cell decline with aging is that, like cellular senescence, it is the result of an evolved balance between cancer and regeneration - which are, after all, two sides of the same coin. Unrestrained growth versus controlled growth. So it has been something of a surprise to find that instructing old, damaged stem cells in old, damaged tissues to act as though young has not produced the immediate enormous risk of cancer that was expected. Still, researchers remain sensibly cautious, as they should given that these approaches to invigorate old cells don't directly address any of the underlying reasons why the cells became quiescent in the first place.

Here is a recent paper on the topic of muscle stem cell rejuvenation that looks at some of the targets and research topics that have been pushed a little way out of the limelight by GDF-11 and its ilk, some of which have interesting associations with cellular senescence in aging - itself a hot topic these days:

Forever young: rejuvenating muscle satellite cells

Extended lifespan raises the issue of handling age-related disorders, which profoundly affect the quality of life of an increasing number of people. At the physiological level, the most relevant feature of aging is the functional decline of tissue functions. In particular, in the elderly, muscle mass declines progressively by means of a process named sarcopenia, making skeletal muscle one of the more compromised tissues during aging. Beyond the protein breakdown associated with the loss of sarcomeric proteins, aged muscles display compromised regenerative capacity associated with altered environmental cues.

Muscle regeneration is achieved by the interplay between adult stem cells, named muscle satellite cells (MuSCs), and other cellular types (i.e. macrophages and muscle interstitial cells) that participate in the orchestration of regeneration. Muscle niche derived and systemic cues contribute to regulate muscle homeostasis and functionality. In order to ensure optimal performance, it is critical that several properties of MuSCs are finely regulated and coordinated. Amongst these properties are survival, self-renewal, fine-tuning between exit from quiescence and proliferative expansion, and eventually commitment toward myogenic differentiation. All these processes are altered in the elderly leading to compromised muscle functionality.

Beyond the notion provided by parabiosis experiments that circulating systemic factors are able to restore muscle regeneration in aged mice, recent evidence supports the hypothesis that MuSCs are intrinsically defective in aged muscles. These new findings open the possibility to target this stem cell compartment to counteract functional decline of muscle during aging.

Research has provided evidence that constitutive activation of the p38 MAPK in aged MuSCs leads to a decline in their self-renewal and regenerative capacity. Partial pharmacological inhibition of p38 is sufficient to restore the ability of MuSCs to participate efficiently in muscle regeneration and to maintain the stem cell pool. Interestingly, an alteration of the FGF-2/FGFR1 axis was identified as a feature of aged MuSC dysfunction. Earlier authors suggest that increased activity of FGFR1 results in the disruption of MuSC quiescence in aged muscles, but recent work supports the hypothesis that FGF-2 increase in the aged niche is a compensatory response to the loss of function of FGFR1 activity observed in aged MuSCs.

Other recent work has demonstrated that geriatric MuSCs fail to support muscle regeneration and display defective activation. Serial transplantation experiments supported the conclusion that this defect is a cell intrinsic feature of geriatric MuSCs. The authors identify the master regulator of senescence p16INK4a as a key determinant responsible for a quiescence-senescence switch (a process named geroconversion) operating in geriatric MuSCs in coincidence with their impaired regenerative potential. Indeed, genetic inactivation of p16INK4a locus was sufficient to recover the cells from the senescence-associated cell cycle arrest and restore their self-renewal capacity, leading to the reconstitution of the stem cell pool after muscle damage. The novelty of this study relies on the finding that geriatric stem cells are associated with the progressive accumulation of DNA damage and senescence-associated markers that in turn contribute to the loss of reversible quiescence mediated by p16INK4a.

These studies demonstrate that in addition to the regenerative environment that profoundly affects the niche and stem cell function, there is another level of tissue homeostasis regulation that is intrinsic to adult stem cells. The cell autonomous functionality declines in the elderly due to de-regulated p38 signaling and accumulation of DNA damage and senescence-associated features. This evidence suggests new avenues to reverse the dysfunctional status of MuSCs from aged tissues. For instance, constitutive FGFR1 signaling can restore MuSCs asymmetric division and self-renewal, and pharmacological blockade of p38 signaling can promote MuSCs self-renewal and engraftment by silencing p16INK4a, thus reversing geroconversion and allowing MuSCs to support muscle regeneration.

Researchers have in the past determined that psychological stress is associated with shorter telomere length as measured in immune cells from a blood sample, and greater ill health in general, but there remains considerable uncertainty over the mechanisms involved. There is also a fair degree of research demonstrating associations between personality traits such as conscientiousness and measures of aging. To what degree is this outcome biological versus being based on factors such as failing to take good care of your health? This review of data on posttraumatic stress disorder (PTSD) looks at much the same question:

PTSD is associated with number of psychological maladies, among them chronic depression, anger, insomnia, eating disorders and substance abuse. Now researchers suggest that people with PTSD may also be at risk for accelerated aging or premature senescence. "This is the first study of its type to link PTSD, a psychological disorder with no established genetic basis, which is caused by external, traumatic stress, with long-term, systemic effects on a basic biological process such as aging."

The majority of evidence fell into three categories: biological indicators or biomarkers, such as leukocyte telomere length (LTL), earlier occurrence or higher prevalence of medical conditions associated with advanced age and premature mortality. In their literature review, researchers identified 64 relevant studies; 22 were suitable for calculating overall effect sizes for biomarkers, 10 for mortality. All six studies looking specifically at LTL found reduced telomere length in persons with PTSD.

The scientists also found consistent evidence of increased pro-inflammatory markers, such as C-reactive protein and tumor necrosis factor alpha, associated with PTSD. A majority of reviewed studies found increased medical comorbidity of PTSD with several targeted conditions associated with normal aging, including cardiovascular disease, type 2 diabetes, gastrointestinal ulcer disease and dementia. Seven of 10 studies indicated a mild-to-moderate association of PTSD with earlier mortality, consistent with an early onset or acceleration of aging in PTSD.

Link: http://www.eurekalert.org/pub_releases/2015-05/uoc--psd050415.php

Here is a very accessible position paper from the Longevity Science Advisory Panel, a UK group interested in medical intervention in the aging process. You'll need to click through to download the full PDF version:

Understanding ageing is demanding. Within it is the paradox that all species, including humans, strive for survival but ageing and death are almost universal in the living world. In this paper we summarise a range of theories and mechanisms of ageing. There is little evidence that it is programmed into our genes and substantial evidence that it is malleable, in that lifespan has been lengthened by a variety of means in a variety of species. Just as important as the process itself is the fact that ageing is associated with an increased risk of many life-threatening diseases. If ageing can be delayed then it is likely that there will be a delay in the development of some or all of these diseases, leading to increased longevity.

Our goal for this project was to produce a report about the complex processes involved in ageing. We wanted it to be accessible to a wide spectrum of readers, not just those involved in academic study. We carried out an unusual research project which involved interviewing eight respected biogerontologists to identify current knowledge about the biology of ageing, which treatments may show promise in delaying the ageing process, and what they see as the future outcomes from scientific research on this topic. We supplemented these expert views with evidence from published studies on the effectiveness of the most promising new anti-ageing treatments, and developed a model to show what this might mean for the extension of human lifespan in the future.

From this research we have been able to build up a picture of the latest developments in this area. The experts tended to agree on which possible factors are important in understanding the biology of ageing. However, they did not necessarily agree on which are the most important components of the ageing process, or on which interventions might have the greatest potential for extending lifespan.

Link: http://www.longevitypanel.co.uk/viewpoint/what-is-ageing-can-we-delay-it/

In aging research, just as in any field of science where much is left to discover and catalog, and where the pace of discovery is slow in comparison to the size of the territory left to map, you will find a promiscuous proliferation of theories and hypotheses. A well constructed theory of aging can last for decades waiting to be disproved, all the while spawning variants and competitors. Hypotheses come and go almost like fashions when the time taken to gather sufficient evidence to swing the pendulum one way or another can extend for a sizable fraction of a researcher's career. This is something to bear in mind when reading any discussion of theories of aging: you are looking at a snapshot of science in development, the final answer still unsettled, all too many details yet to be filled in robustly and defensibly.

The present consensus position on aging is that it is caused by an accumulation of damage. There are probably a score of good theories discussing exactly what damage is involved, and how important various different types of damage might be. There are another score of outdated, or dubious, or too narrowly focused, or myopic theories on aging as damage beyond that circle. On the small scale there are a hundred debates over cellular and tissue damage with relation to aging, all of which are waiting on better data for one side to declare a definitive victory. That will happen for some of these issues over the next decade, with the damage caused by cellular senescence being one of the next in line, I'd imagine.

At the large scale, the big debate is between the majority position of aging as damage accumulation versus the minority position of aging as an evolved program that causes damage. This division emerges from work on evolutionary theories of aging, which are as much focused on trying to explain the origin and history of aging as on the precise mechanisms involved. Nonetheless this seems to me more important to the near future of efforts to treat aging as a medical condition than divisions within the aging-as-damage community. This is because the recommended strategy for treating aging that emerges from the programmed aging view is very different, and probably ineffective if aging is indeed damage accumulation.

In the programmed aging framework the best approach to rejuvenation is to identify changes in metabolism characteristic of old age and try to revert them to youthful configurations, such as through pharmacological interventions to change the levels of circulating proteins. In that view, changing the operation of metabolism to a more youthful track should cause damage accumulation to cease and existing damage to be repaired to at least some degree. From the perspective of aging as damage accumulation, altered levels of circulating proteins are a reaction to damage, however, and thus aiming to alter them is putting the cart before the horse - it is targeting consequences rather than causes, and should thus be largely ineffective in comparison to direct efforts to repair the damage.

Ironically much of the research community adheres to the view of aging as damage, but for historical and regulatory reasons these scientists follow research strategies that are more suited to the programmed aging playbook. If you survey the laboratories involved in aging research you are far more likely to find researchers developing drugs to alter protein levels than you are to find researchers trying to repair the recognized forms of cellular and tissue damage. This must change, I believe, if we are to see meaningful progress in our lifetimes.

Theories of Aging: An Ever-Evolving Field

Senescence has been the focus of research for many centuries. Despite significant progress in extending average human life expectancy, the process of aging remains largely elusive and, unfortunately, inevitable. In this review, we attempted to summarize the current theories of aging and the approaches to understanding it. A number of theories, which fall into two main categories, have been proposed in an attempt to explain the process of aging. The first category is comprised of concepts holding that aging is programmed and those positing that aging is caused by the accumulation of damage. Conversely, the latter category of theories suggests various sources and targets of the damage. They are not necessarily mutually exclusive. Rather, aging could vary across different species, and programmed senescence can accelerate the buildup of damage or decrease the capacity for repair.

Most obviously, the average lifespan within a given species is genetically programmed in one way or the other. Nevertheless, the current theories of aging differ in viewing aging as a consequence or a side effect of genetic pathways. According to the well-known disposable soma theory, aging is a trade-off in the allocation of limited energy resources between maintenance and restoration of tissue homeostasis and other traits needed for survival. This trade-off is demonstrated when comparing the mean lifespan of related animal species with different predation risks. When the risk is high, delayed senescence has no added benefit relative to, for example, rapid reproduction.

Nearly all current theories of aging have in common the fact that the fundamental cause of aging is the accumulation of molecular damage brought about mainly by reactive oxygen species, but the role of amyloid protein, glycation end-products, and lipofuscin is acknowledged as well. The current theories differ in the extent to which the buildup of waste is encoded in the genome and whether it is programmed death or this accumulation that is deemed to bear the costs of evolutionary benefits. In addition to damage itself, the rate of accumulation is also of concern, which results from overall metabolic activity. The most significant changes in the longevity of model organisms prove to be mutations in metabolic pathways.

One of the distinguishing features of old tissues is the presence of solid protein aggregrates. In some cases these are clearly linked to the pathology of specific diseases, such as Alzheimer's or forms of amyloidosis. For others no clear association with age-related dysfunction has yet been found. It seems prudent to develop means to remove these aggregates regardless, and this is one of the pillars of the SENS approach to rejuvenation treatments. In this paper, researchers propose that not all aggregates are equal, and some are the result of protective mechanisms that sequester an excess of proteins created through age-related dysfunction, rather than being a form of damage in and of themselves:

Researchers used the tiny nematode worm Caenorhabditis elegans as a model organism to analyse the changes that occur in the proteome (the entirety of all proteins) during a lifespan. "The study is the most extensive of its kind in a whole organism quantifying more than 5,000 different proteins at multiple time points during aging." The researchers were able to show that the proteome undergoes extensive changes as the worms age. About one third of the quantified proteins significantly change in abundance. The normal relation between different proteins, which is critical for proper cell function, is lost. This shift overwhelms the machinery of protein quality control and impairs the functionality of the proteins. This is reflected in the widespread aggregation of surplus proteins ultimately contributing to the death of the animals.

Based on these findings, the researchers also analysed how genetically changed worms with a substantially longer or shorter lifespan manage these changes. "We found that proteome imbalance sets in earlier and is increased in short-lived worms. In contrast, long-lived worms coped much better and their proteome composition deviated less dramatically from that of young animals." Surprisingly, the long-lived worms increasingly deposited surplus and harmful proteins in insoluble aggregates, thus relieving pressure on the soluble, functional proteome. However, in contrast to the aggregates found in short-lived animals, these deposits were enriched with helper proteins - the so-called molecular chaperones - which apparently prevented the toxic effects normally exerted by aggregates.

"These findings demonstrate that the cells specifically accumulate chaperone-rich protein aggregates as a safety mechanism. Therefore, the aggregates seem to be an important part of healthy aging." Indeed, it is known that insoluble protein aggregates also accumulate in the brains of healthy elderly people. So far, researchers assumed that neurodegeneration and dementia appear to be mainly caused by aberrant protein species accumulating in aggregates. This assumption may now be tested again: "Clearly, aggregates are not always harmful. Finding ways to concentrate harmful proteins in insoluble deposits might be a useful strategy to avoid or postpone neurodegenerative diseases as we age."

Link: http://www.mpg.de/9218809/protein-aggregates-cells-aging

Regular moderate exercise extends healthy life span and slows many of the declines associated with aging. This is at least in part due to mitochondrial processes:

Inactivity accelerates muscle catabolism, mitochondrial dysfunction, and oxidative stress accumulation and reduces aerobic capacity . These problems can lead to a "vicious circle" of muscle loss, injury, and inefficient repair, causing elderly people to become increasingly sedentary over time. Thus, it is imperative to implement preventive and therapeutic strategies to boost muscle mass and regeneration in the elderly and hence maintain and improve both their health and independence and prevent the occurrence of the frailty condition.

Current evidence certainly indicates that a regular exercise program reduces and/or prevents a number of functional declines associated with aging. Since, besides genetic, environmental, and nutritional factors, the lack of physical activity plays a major role in the pathophysiology of frailty, regular exercise has also the potential to reduce the incidence of this problematic expression of population aging. Older adults can adapt and respond to both endurance and strength training. Aerobic/endurance exercise helps to maintain and improve cardiovascular and respiratory function, whereas strength/resistance-exercise programs have been found to be helpful in improving muscle strength, power development, and function.

In this review we describe the pleiotropic effect of physical activity on multiple targets that have a role in preventing the decline of mitochondrial "quality," which is implicated in the aging process of skeletal muscle. Recent evidences consistently show that the "quality" of skeletal muscle mitochondria declines during aging. Indeed, in this condition we can observe (i) mitochondrial DNA mutations; (ii) specific epigenetic drift; (iii) decreased expression of mitochondrial proteins; (iv) reduced enzyme activity of cellular respiration; (v) reduced total mitochondrial content; (vi) increased morphological changes; (vii) a decrease in mitochondrial turnover. All of these factors probably contribute to age-associated sarcopenia, and a growing body of evidence suggests that most of these skeletal muscle age-related changes can be prevented and or attenuated by physical activity. In short, physical activity should be prescribed for older adults. It not only improves physical function, helping the elderly to maintain independence, but also enhances overall health and increases longevity.

Link: http://dx.doi.org/10.1155/2015/917085

Longevity science, work on the foundations of rejuvenation therapies to extend healthy life, isn't a special snowflake in any way. It isn't magically separate, distinct, and remote from other areas of medicine. It has exactly the same goals, which are to prevent suffering and death. It builds upon the same modern understanding of cellular biochemistry. Also, just like near all medical research, it is ignored by most people most of the time, despite the fact that everyone's future health is absolutely dependent on advances in medical science.

Medicine is pivotal, and yet you might not think so given the tiny fraction of a fraction of overall expenditures that we devote to the task of improving medical technologies, of building new and better treatments. Every improvement in the technologies of health that we rely upon here and now was constructed with scraps and leftovers of funding, accomplished in spite of a vast and bland indifference on the part of the public at large. Vast sums are devoted to decorations and frivolity in place of building better medicine. It is unfortunately human nature to fixate upon circuses, politics, and distractions, on things that matter very little in comparison to the life and death work of finding cures for fatal medical conditions.

Fatal medical conditions such as degenerative aging, for example. The one that everyone suffers from, and which will kill more than nine-tenths of everyone you know, after decades of increasing pain and disability, should you be fortunate enough to live in one of the wealthier parts of the world. Going by the way most people act, this isn't a big deal. Even the most horrible situations will be accepted, even defended, if they happen to be the long-standing present status quo, and aging is perhaps the best example of this phenomenon. If you didn't have it, would you volunteer for it? The years of decline and pain, the corrosion of the mind, the eventual drawn out death? That would be crazy. Yet you don't have to wander far today to find people praising aging and eventual death as a wonderful and proper set of circumstances.

Kicking our societies out of the present status quo and into a better one is left to the rebels, the iconoclasts, and other varieties of unreasonable visionary. This has been underway in earnest for decades now in the matter of bringing aging under medical control, and change is coming. The ranks of those willing to speak out and act are growing, both within and outside the life science community. There are still all too many people who see at least a little of the possibilities for the future but do nothing but hope in private, however. Hope on its own achieves nothing: the future you desire won't just happen by itself. The future is what we choose to build, and those who act are those who build it.

Futurist: I will reap benefits of radical life extension

The idea of people [routinely] living deep into their 70s is relatively new, dating back, according to World Bank statistics, to only the 1960s in the U.S. In developing parts of the world, that long of a life is still a dream. But today, enterprising scientists and brash thinkers are considering a life far longer, pondering a future where people in all parts of the globe regularly live deep into their 100s. Research institutes (such as the Buck Institute for Research on Aging in California), charitable foundations (like the SENS Research Institute and Glenn Foundation for Medical Research) as well as companies (like Google) are all pouring money into work to understand, counteract and delay aging.

This idea, immortality, has been around seemingly forever. What's different about it today, this quest?

What makes discussions about radical life extension, I think, different today is that it's transcended the spiritual realm, it's transcended the supernatural. It was something that didn't really have any basis in science or technology, it was more of a longing, a desire to live forever whether it be in this world or in some alternate world. The big difference now of course is that we're starting to have a sense of the technologies, the science, that could make this happen.

But isn't that something that every generation believes - that they're closer than ever to solving aging? Can you convince a cynic that there's something real here?

I think there is a big difference between what we're accomplishing today as opposed to what was done a hundred or two hundred years ago. We are actually, over the last hundred years - actually, specifically, even maybe the last 50 - we're starting to develop medical technologies that are genuinely prolonging life. Whether it be such things as antibiotics and vaccines, and even things like surgery and now artificial organs and so on -most recently of course the advent of stem cells and regenerative medicine. These are on an order of scale far different than what we've seen in the past. We have seen the first developments of bona fide life-extension technologies.

It seems like most of the people seeking to fight aging, they're tech guys, not doctors. It's not like they're a minority of doctors, they're a completely different community.

There are many reasons the medical community would wish to shy away from this conversation. One, this is still very fringe. It's not something accepted in the medical community that you could actually cure aging. Aging is not even looked at as a disease, for example. This is the paradigm shift that's currently happening - yes, we are looking at it as a disease that can be defeated. That's the shift that is going to have to be made within the medical community.

Right now, each and every specialist, whether they are looking at neurological disorders or looking at cardiovascular problems, or diabetes or what have you, they're very focused on that particular area and they don't necessarily see the big picture of it all. Yet the irony of it is that every one of these specialists is contributing to what will be a therapy that will be used to prolong life. This would be a suite of therapies that would tackle every facet of aging, and as we know, we're learning on a regular basis that aging is a multifaceted process that affects so many different parts of our bodies.

Eventually I think that once we get over the inhibition or the taboo of talking about radical life extension, and the idea that we can live forever, I think we'll see the medical community and individuals in medicine start to talk a bit more openly and frankly about the possibilities. It'll start to become ridiculous not to do so.

Take the haves and the have-nots: As these technologies come out, who will have access to them and who won't? You have to assume those with money will probably have access to them.

As we've seen time and time again, the first generation or two of any technological development, whether it be a gadget that you can get at your technological store, whether it be medical advances, is pretty much reserved for those who have the money to pay for it. So I think that it's good that we're talking about it now. It surely shouldn't be something that will preclude these technologies from being developed.

The mentality that if a few people can't have it, nobody should be able to have it, is really a facile argument and really should be shoved away as quickly as possible. The larger issue is how quickly can we make these technologies available to as wide a group of people as is possible, that's absolutely fundamental to this discussion.

Be someone who acts, that's my advice. Find a way to help, and then do so, whether that is raising funds for SENS rejuvenation research, or persuading a friend to see aging in a different light, or writing for the public at large. The more of us there are, the shorter the span of time between now and the first therapies that will control, halt, and reverse the consequences of aging.

Mitochondria are biological power plants, swarming and multiplying in their hundreds like bacteria inside every cell. They contain a little DNA, separate from that in the cell nucleus, and some forms of damage to that DNA result in cells taken over by malfunctioning mitochondria. These faulty cells increase in number over a lifetime, exporting damaged molecules far and wide in the body, and contributing to numerous aspects of degenerative aging.

Quality control mechanisms watch over mitochondria and destroy those that become damaged, a process known as mitophagy. Clearly these mechanisms are not perfect and important forms of damage slip through the net. While it is thought that increased cellular housekeeping activity, including mitophagy, is a key contributing mechanism in most of the known methods of slowing aging in mice and other species, it is unclear as to whether this can provide protection against forms of damage to mitochondia that evade mitophagy under normal circumstances. Will they still evade a more active level of mitophagy that is just a greater repetition of the same processes? In part this uncertainty is due to the lack of any methodology to spur the operation of mitophagy in isolation, so as to see what happens without the complication of numerous other changes taking place at the same time. These researchers claim development of such a means:

Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent.

We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245710/

Inhibiting adenylyl cyclase type 5 (AC5) has been demonstrated to extend life in mice. This open access review paper covers what is known of the mechanisms involved:

Adenylyl cyclase (AC) is a ubiquitous enzyme which regulates all organs and catalyzes the conversion of ATP to cAMP. There are nine major mammalian AC isoforms; types 5 and 6 are the major isoforms in the heart. Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against obesity, the cardiomyopathy induced by aging, diabetes, and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection.

Inhibition of AC5 naturally becomes an important mechanism for clinical translation. There have been recent clinical studies supporting our findings in the AC5 KO model. The clinical genome wide association studies have identified single nucleotide polymorphisms (SNPs) in the ADCY5 gene associated with increased type 2 diabetes risk, which is the inverse of AC5 inhibition and therefore consistent with our findings. However, it is difficult to isolate the specific action of one gene in human genome studies, as we have done by disrupting the AC5 gene in mice. Unfortunately disrupting the AC5 gene in patients is not feasible and therefore it becomes necessary to identify a pharmacological inhibitor of AC5. One example of a pharmacological compound that replicates many of the features of AC5 inhibition is an FDA approved antiviral drug, Vidarabine, which protects against the development of cardiomyopathy in mice. However, this drug is not purely an AC5 inhibitor and has the disadvantage that it cannot be administered orally. Accordingly, further work is required to develop a nontoxic AC5 inhibitor that is soluble and can be given to patients orally.

Link: http://dx.doi.org/10.1155/2015/250310

Calorie restriction with optimal nutrition is the practice of eating fewer calories, cutting perhaps a third of those in a normal healthy diet, while still obtaining optimal amounts of essential micronutrients. Calorie restriction reliably extends healthy and maximum life spans by up to 40% in short-lived mammals such as mice and rats. It slows aging and extends life in near all species for which rigorous life span studies have been carried out, in fact. The calorie restriction response seems almost universal in the animal kingdom, with many of the identified mechanisms similar or the same in widely separated species. This is a phenomenon that probably originates a long way back in evolutionary time, in other words. When it comes to longer-lived species such as primates, including we humans, the only truly comprehensive and rigorous data presently to hand covers short-term reactions to calorie restriction, however. It takes a long time to run a life span study for humans or even for our neighboring primates: two calorie restriction studies in rhesus macaques have been running for decades now, and there is some debate over whether the study design has led to data that is too flawed to be useful.

The bottom line question: does calorie restriction extend life in humans? The present consensus in the scientific community is that the answer is probably yes, but not by anywhere near the same degree as in short-lived mammals. From an evolutionary perspective, the calorie restriction response arises because it improves survival in the face of seasonal famine. A season is a large portion of a mouse life span, but not so much time for a human, and thus only the mouse evolves a dramatic plasticity of aging and longevity in response to circumstances. Nonetheless, the cataloged health benefits of calorie restriction in humans are impressive and very similar to those observed in mice. There is no presently available medical technology that can grant the same degree of benefits to a basically healthy individual, when looking at important measures such as blood pressure, resistance to common age-related diseases, and so forth. It is true that you can't reliably live to age 90 and beyond in good health via any lifestyle choice, calorie restriction included, but in the present era of rapid progress in medicine, every extra year that you can win for yourself counts. The line in the sand to separate those who die too soon to benefit from near future rejuvenation technologies and those who just make it will be narrow indeed.

So give a little thought to trying calorie restriction. What do you have to lose? Here are a couple of items pulled from the stack, pointers to recent research into calorie restriction and the health benefits it produces. These are all fairly typical of the field, meaning a narrow investigation of one small aspect of biochemistry, and a confirmation that calorie restriction improves matters by slowing or delaying age-related changes:

SAGE Review: New insights into calorie restriction and its effects on sarcopenia and aging

Researchers reported that calorie restriction in rats has an age-dependent protective effect on age-related muscle loss by improving skeletal muscle metabolism in rats. The authors fed young (4 month) and middle-aged (16 month) rats one of two diets - either a normal diet, ad libitum (AL), or a restricted diet, 40% calorie restriction (CR), for a total of 14 weeks. They found that normalized muscle weight (muscle weight divided by body weight) was lower in normal, AL-fed, middle-aged rats compared to young rats. However, when the two age groups were fed the CR diet, skeletal muscle in middle-aged rats was protected from expected age-related degeneration and muscle mass was comparable to levels of young rats fed the AL diet. Interestingly, CR had a negative effect on normalized muscle weight in young mice and caused a decrease in muscle mass.

It seems that CR has an age-dependent beneficial effect on skeletal muscle mass in rats and can reprogram skeletal muscle metabolism to function at levels that resemble those of young rats fed a normal diet. A more applicable question arising from this study is whether CR can counteract muscle degeneration in middle-aged or elderly humans. This study suggests that middle-aged humans could potentially benefit from a CR diet with respect to preventing muscle loss. Conducting a similar experiment in humans will be a much larger endeavor, however, scientists can use what we learn from these rat studies and other model organisms to better understand metabolic pathways that go awry with aging. Ultimately, understanding the mechanisms behind the beneficial effects of CR and how they influence muscle loss during aging will open the doors for the development of therapies to prevent or treat aging-related diseases.

Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR.

We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.

Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain

Caloric restriction (CR) has been shown to increase the life span and health span of a broad range of species. However, CR effects on in vivo brain functions are far from explored. In this study, we used multimetric neuroimaging methods to characterize the CR-induced changes of brain metabolic and vascular functions in aging rats. We found that old rats (24 months of age) with CR diet had reduced glucose uptake and lactate concentration, but increased ketone bodies level, compared with the age-matched and young (5 months of age) controls. The shifted metabolism was associated with preserved vascular function: old CR rats also had maintained cerebral blood flow relative to the age-matched controls. When investigating the metabolites in mitochondrial tricarboxylic acid cycle, we found that citrate and α-ketoglutarate were preserved in the old CR rats. We suggest that CR is neuroprotective; ketone bodies, cerebral blood flow, and α-ketoglutarate may play important roles in preserving brain physiology in aging.

Studies searching for genetic differences capable of explaining natural variations in human longevity, such as the existence of long-lived families, have turned up little in the way of consistent results. Associations in one study rarely replicate in other study populations, even in the same geographic regions. This most likely means that genetic contributions to longevity are numerous, individually tiny, and have a complicated set of relationships with one another. There is no easy road to enhanced longevity here:

Longevity is an extremely complex phenotype that is determined by environment, life style and genetics. Genome wide association studies (GWAS) have been a powerful tool to identify the genetic origin of other complex outcome with a similar heritability. Here we discuss the findings all GWAS of longevity conducted to date. Various cut-off to define longevity have been used varying from 85+, 90+ and 100+ years and the impact of these difference are addressed. The only consistent association emerging from GWAS to data is the APOE gene that has been already identified as a candidate gene. Although (GWAS) have identified biologically plausible genes and pathways, no new loci for longevity have been conclusively proven.

A reason for not finding any replicated associations for longevity could be the complexity of the phenotype, although heterogeneity also underlies many other traits for which GWAS has been successful. One may argue that rare variants explain the high heritability of longevity and the segregation of the trait in families. Yet, whole genome analyses of GWAS data still suggest that over 80% of the heritability is explained by common variants. Although findings of GWAS to date have been disappointing, there is ample opportunity to improve the statistical power of studies to find common variants with small effects. In the near future, joining of the published studies and new ones emerging may surface new loci.

Link: http://dx.doi.org/10.1007/978-1-4939-2404-2_5

This report from a recent symposium is a good reminder that the majority of work in the aging research community has little or no relevance to the goal of extending healthy human longevity by a large amount. There are very few research programs that offer the possibility of adding decades of healthy life to the present human life span if followed through to completion, and the SENS projects are so far the only coherent, well-organized example of those. The average research organization is conducting work much more in line with the projects noted below:

What have we learned about aging during the past few decades and where is that knowledge taking us as society continues to skew older? To answer those questions, the USC Davis School of Gerontology hosted "What's Hot in Aging Research at USC," the sixth annual interdisciplinary symposium at the Ethel Percy Andrus Gerontology Center. Faculty members shared their current research, offering insight as to how it would impact older adults, their families and communities in the future.

The morning session opened with a discussion of the biological mechanisms behind aging, life span and aging-related disease. Valter Longo, Edna M. Jones Professor and USC Longevity Institute director, emphasized the importance of understanding the basic mechanisms of aging, not just hunting for specific remedies for aging-related diseases such as diabetes and cancer. As the population as a whole grows older, many of humanity's most important health challenges will be rooted in the aging process, and researchers will need to "go after the aging process itself, not just Band-Aid solutions," he said.

University Professor Caleb Finch and Professor Christian Pike described their research into inflammatory responses in the brain and Alzheimer's disease. Finch has been exploring the possible links between pollution-induced inflammation and the disease, while Pike has probed the connections between obesity and increased expression of inflammatory factors that heighten Alzheimer's risks. Assistant Professor Sean Curran discussed his work on the interaction of diet and genetics, outlining the possible translational path his studies would take from C. elegans to humans, highlighting the possibilities for personalized nutritional insight ushered in by the genomics revolution. "Every person in every environment is different. If you have a variation in specific genes, how is that predictive of what diet will give you maximum success?"

Addressing several myths about longevity, Assistant Professor Jennifer Ailshire said that although the portion of the population reaching age 100 is still tiny, more people are reaching the milestone than ever. Demographics show that some who become centenarians can reach old age in relatively good health and don't simply spend more years in poor health than others.

Link: https://news.usc.edu/80577/aging-symposium-examines-alzheimers-longevity-and-independence/

DNA methylation, the decoration of DNA with methyl groups, is one of the mechanisms involved in epigenetic control over production of proteins from their blueprint genes. A cell is a factory packed with levers, dials, and feedback loops, most of which involve the amounts of specific proteins present in the cell and its surrounding environment. Cell behavior changes from moment to moment in reaction to circumstances, and epigenetic alterations such as DNA methylation regulate these changes by altering rates of protein production.

Over the past five or six years a number of researchers have made inroads in the use of patterns of DNA methylation as a measure of either biological age or chronological age. If we consider aging to be caused by an accumulation of damage to cells and tissue structures, then we should expect certain characteristic patterns of epigenetic alterations to emerge in response. Everyone ages due to the actions of the same underlying processes, and while most DNA methylation appears to be highly individual, patterns nonetheless emerge.

All of this is of interest to the aging research community because there is a great need for accurate ways to measure biological age. Testing proposed treatments that might slow or reverse aging takes far too long at the present time, requiring animal studies that last for years and cost millions to gain even a vague idea as to how effective any given treatment might be. If there was an agreed upon way to reliably measure the systematic reaction to higher levels of damage in an aged individual, then new therapies could be rapidly filtered for those that actually make a difference. To my eyes that should mean therapies that repair the forms of damage known to cause aging. I see a good marker for biological age as something that could bring an end to much of the debate over causes of aging, which causes are more important, and which strategy for the development of treatments should be pursued. A great deal of the present diversity of opinion and theory would evaporate in the face of better data.

On this topic, here is a very readable open access review paper that covers the recent history of work on DNA methylation as a measure of aging. As it makes clear, finding DNA methylation patterns that look promising is only the start of the process of producing an acceptable standard of measurement for aging:

DNA methylation and healthy human aging

The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor.

DNA methylation changes that are associated with age can be considered part of two related phenomena, epigenetic drift and the epigenetic clock. We have defined epigenetic drift as the global tendency toward median DNA methylation caused by stochastic and environmental individual-specific changes over the lifetime. The epigenetic clock, on the other hand, refers to specific sites in the genome that have been shown to undergo age-related change across individuals and, in some cases, across tissues.

A number of aspects of age-related DNA methylation remain, which should be further scrutinized. First, it is expected that certain life periods, such as early childhood, puberty, and advanced age, result in accelerated epigenetic changes. Most studies of DNA methylation and age have examined changes within specific periods of life - the first few years of life or adulthood to old age, for example. Moving forward, it will be important to determine what periods during the lifespan are the most changeable, which highlights the need for more rigorous studies. Moreover, work on the effects of environmental stimuli on the rates of epigenetic aging would contribute insight into how or why specific environmental exposures result in increased mortality. It could be hypothesized that people who are exposed to factors that affect mortality show advanced epigenetic compared to chronological age, although these effects may be tissue specific.

Several recent cross-sectional studies have published epigenetic clocks. Comparison of these sites across longitudinal studies, while controlling for confounders in DNA methylation such as tissue type, cellular composition, ethnicity, and environment, is necessary to confirm a consistent, reliable, and independent signature of DNA methylation and aging. This type of age predictor could be of use in a number of areas. In health, epigenetic age could be used to target or assess interventions or treatments. However, the health-related potential of epigenetic age still waits on an assessment of concordance between epigenetic and chronological age across a large population with longitudinal tracking of health during the aging process. This field has immense potential to inform human populations and will undoubtedly continue to develop in the near future.

With advancing age an ever greater number of cells in the body linger in a senescent state in which replication is halted rather than destroying themselves after reaching the Hayflick limit. This can be a reaction to cellular damage or potentially damaging tissue environments, and at least initially helps to lower the incidence of cancer by preventing cells that are potentially at risk from continuing to replicate. Unfortunately senescent cells secrete a range of proteins that degrade surrounding tissue and encourage nearby cells to also become senescent. Given large enough numbers of senescent cells this activity leads to meaningful loss of function in important organs and contributes to the development of age-related disease.

In recent years researchers have demonstrated benefits to health and healthy life span resulting from selective clearance of senescent cells in mice, and removing senescent cells is one of the targets of the SENS rejuvenation research program. Here scientists link cellular senescence to mechanisms known to contribute to glaucoma, a form of blindness caused by raised fluid pressure inside the eye and resulting nerve damage:

The most common form of glaucoma, primary open angle glaucoma, is an aging associated disease often characterized by elevated intraocular pressure induced by increased outflow resistance of the aqueous humor. The human trabecular meshwork (HTM), a complex three-dimensional structure comprised of cells, interwoven collagen beams and perforated sheets, is believed to provide the majority of outflow resistance in both normal and glaucomatous eyes. HTM cells, depending on the region of the HTM, either form sheets covering extracellular matrix (ECM) structures or are scattered throughout the ECM. What changes in the HTM resulting in increased resistance is poorly understood, but our recent study showed the HTM is ~20 fold stiffer in glaucoma, suggesting a prominent role of HTM mechanobiology. This tissue-scale stiffening is likely a result of biophysical changes to both the ECM and constituent cells, as structural changes to both the cytoskeleton and ECM have long been associated with glaucoma.

Building upon these findings, further research has led to a growing body of evidence that these biophysical changes are not epiphenomena, but upstream of factors important in the progression of the disease. A prime candidate for this process is cellular senescence, the irreversible arrest of cellular proliferation. Senescence is thought to contribute to many of the physiological changes associated with aging as well as aging associated disease. In this study, primary HTM cells were serially passaged until senescence and atomic force microscopy (AFM) was used to measure the intrinsic mechanical properties of senescent cells compared to normally proliferating controls. We found that stiffness was significantly increased in high passage HTM cells. In aggregate, these data demonstrate that senescence may be a causal factor in HTM stiffening and contribute towards disease progression. These findings provide insight into the etiology of glaucoma and, more broadly, suggest a causal link between senescence and altered tissue biomechanics in aging-associated diseases.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=3798&path%5B%5D=8094

For some years now researchers have been investigating the biochemistry of species such as salamanders and zebrafish that are capable of regrowing limbs and internal organs. It is as yet unknown how hard it will be to improve human regenerative capacity using what is learned from this research, but definitive answers may emerge over the next decade:

While the human heart can't heal itself, the zebrafish heart can easily replace cells lost by damage or disease. Now, researchers have discovered properties of a mysterious outer layer of the heart known as the epicardium that could help explain the fish's remarkable ability to regrow cardiac tissue. After an injury, the cells in the zebrafish epicardium dive into action - generating new cells to cover the wound, secreting chemicals that prompt muscle cells to grow and divide, and supporting the production of blood vessels to carry oxygen to new tissues.

Researchers found that when this critical layer of the heart is damaged, the whole repair process is delayed as the epicardium undergoes a round of self-healing before tending to the rest of the heart. "The best way to understand how an organ regenerates is to deconstruct it. So for the heart, the muscle usually gets all the attention because it seems to do all the work. But we also need to look at the other components and study how they respond to injury. Clearly, there is something special about the epicardium in zebrafish that makes it possible for them to regenerate so easily. The epicardium is underappreciated, but we think it is important because similar tissues wrap up most of our organs and line our organ cavities. Some people think of it as a stem cell because it can make more of its own, and can contribute all different cell types and factors when there is an injury. The truth is we know surprisingly little about this single layer of cells or how it works. It is a mystery."

The new research showed that the process requires signaling through a protein called sonic hedgehog, and demonstrated that adding this molecule to the surface of the heart can drive the epicardial response to injury. Researchers also found that the epicardium produces a molecule called neuregulin1 that makes heart muscle cells divide in response to injury. When they artificially boosted levels of neuregulin1, even without injury, the heart started building more and more muscle cells. The finding further underscores the role of this tissue in heart health. The researchers now plan to perform larger screens for molecules that could enhance heart repair in zebrafish, and perhaps one day provide a new treatment for humans with heart conditions.

Link: http://today.duke.edu/2015/05/heartlayer

When reading about research into any particular gene or protein and its influence on aging it is important to keep in mind that our biochemistry is a network of connections. Nothing happens in isolation, and any change in the amount of a particular protein or interference in its activities will cause a cascade of consequences though its interactions with other proteins. Thus there are probably comparatively few important mechanisms involved in determining natural variations in longevity but many distinct ways to manipulate those mechanisms.

Decades of research focused on treating cardiovascular disease and hypertension have resulted in a range of drugs that interfere with the activities of angiotensin II and the broader renin-angiotensin system it is a part of. These biological systems have a fairly direct role in determining blood pressure, and hence have long been a target for efforts to slow down the onset of hypertension. Thanks to the easy availability of drugs targeting the renin-angiotensin system, a fair amount of research has taken place into the effects of these interventions on aging in mice. Disrupting an angiotensin II receptor increases mouse life span, for example, as does a reduction in levels of ACE, the angiotensin I-converting enzyme responsible for transforming angiotensin I into angiotensin II. These interventions may work to extend life by reducing blood pressure, and may have other important effects involving enhanced mitochondrial function.

Definitive answers as to how specific approaches to alter the operation of metabolism actually work under the hood so as to extend life span are slow in arriving, however. Cellular biochemistry is enormously complex, so much so that it is par for the course for a decade or more to come and go without too much progress being made in understanding how a particular mechanism influences longevity. This is the case for angiotensin II and the systems it participates in. Below are linked a few recent papers on the topic; they don't add a great deal over similar papers published ten years ago, beyond reinforcing the point that high blood pressure is a potent source of tissue damage in old age, and being more openly enthusiastic about building treatments for aging:

The Intrarenal Renin-Angiotensin System in Hypertension

The renin-angiotensin system (RAS) is a well-studied hormonal cascade controlling fluid and electrolyte balance and blood pressure through systemic actions. The classical RAS includes renin, an enzyme catalyzing the conversion of angiotensinogen to angiotensin (Ang) I, followed by angiotensin-converting enzyme (ACE) cleavage of Ang I to II, and activation of AT1 receptors, which are responsible for all RAS biologic actions.

Recent discoveries have transformed the RAS into a far more complex system with several new pathways. Instead of a simple circulating RAS, several independently functioning tissue RASs exist, the most important of which is the intrarenal RAS. Several physiological characteristics of the intrarenal RAS differ from those of the circulating RAS, autoamplifying the activity of the intrarenal RAS and leading to hypertension.

Angiotensin II Blockage: How its Molecular Targets May Signal to Mitochondria and Slow Aging

Caloric restriction (CR), rapamycin-mediated mTOR inhibition and renin angiotensin system blockade (RAS-bl) increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated to their physiological benefits. mTOR-inhibition and enhanced sirtuin and Klotho signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference.

Here we review how mTOR-inhibition extends lifespan, Klotho functions as an aging-suppressor, sirtuins mediate longevity, Vitamin-D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR, upregulates Klotho, sirtuin and VitaminD-receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, klotho and sirtuin expression and Vitamin-D signaling, paralleling CR actions in age retardation.

Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease.

Pleiotropic Effects of Angiotensin II Receptor Signaling in Cardiovascular Homeostasis and Aging

Most of the pathophysiological actions of angiotensin II (Ang II) are mediated through the Ang II type 1 (AT1) receptor, a member of the seven-transmembrane G protein-coupled receptor family. Essentially, AT1 receptor signaling is beneficial for organismal survival and procreation, because it is crucial for normal organ development, and blood pressure and electrolyte homeostasis. On the other hand, AT1 receptor signaling has detrimental effects, such as promoting various aging-related diseases that include cardiovascular diseases, diabetes, chronic kidney disease, dementia, osteoporosis, and cancer. Pharmacological or genetic blockade of AT1 receptor signaling in rodents has been shown to prevent the progression of aging-related phenotypes and promote longevity. In this way, AT1 receptor signaling exerts antagonistic and pleiotropic effects according to the ages and pathophysiological conditions.

The SENS model of aging, and the resulting research programs aimed at producing rejuvenation treatments, are predicated on identifying the forms of cellular and tissue damage that are the initial, primary cause of aging. This means damage that occurs directly as a result of the normal operation of healthy metabolism, and excludes damage that occurs as a secondary consequence of other forms of damage. There is arguably a far greater variety of secondary damage than primary damage, which is only to be expected given the complexity of living organisms. Simple damage in a complex system produces complex results. This is why SENS can be viewed as a shortcut to meaningful results in treating aging: it is focused on a narrow, fairly well understood, and simpler region of our biology. The hope is that in repairing the primary forms of damage, most of the secondary forms of damage will then be repaired by our own maintenance mechanisms.

You don't have to dive too far into the research literature to find grey areas and unknowns, however. There are a number of forms of damage that could be either primary or secondary harms, and finding out which is the case still lies somewhere in the future. If funding for SENS research was far greater than it is now, then it would make sense to open repair programs for all of the ambiguous forms of damage: err on the side of caution and fix everything. Since funding is still minimal, however, the most cost-effective path is to work on fixing the definitive forms of primary damage and then see how that affects other forms of damage and change that occur in aging.

Q: A lot of tissues, including notably the arteries, develop calcium deposits with age. Isn't this also an important kind of aging damage? Don't you need to develop a new rejuvenation biotechnology to remove it from our tissues?

A: To answer the question, we first need to disaggregate (no pun intended) the general category of "calcification." There are quite a few tissues that calcify to some degree in most or all aging people, and the reasons why this occurs and the nature of the structural disruption it causes are quite distinct depending on the tissue. In fact, even looking at just the arteries, there are several different kinds of "arterial calcification," including calcification connected with atherosclerotic plaque and calcification of the fibrils of elastin protein that loan the arteries their elasticity.

It's unlikely that all of these are true aging damage, but it's quite plausible that at least some of them are. The key question is whether each of these calcified deposits are really an intrinsically more or less irreversible change, or if like many other things that go wrong in aging they're sufficiently dependent on other, primary age-related changes that they would revert to the healthy norm if the original insult were resolved. In the former case, we would indeed need to develop rejuvenation biotechnologies to remove them. But it seems likely that some forms of age-related tissue calcification occur and are sustained by the effects of other forms of aging damage or the body's responses to them - things like oxidative stress caused by accumulation of cells that have been taken over by mutant mitochondria, or the inflammatory secretions of senescent cells. If calcification is driven and perpetuated by the effects of other, primary kinds of aging damage, then all we will really have to do is remove or repair the original aging damage, and the downstream calcification will resolve itself "for free" (or the body's natural repair and maintenance machinery will do it for us).

The more well-understood form of arterial calcification, for instance, is pretty clearly a secondary effect of local atherosclerotic lesions, and driven by inflammation. Once we clear the oxidized cholesterol products from atherosclerotic foam cells and allow them to egress, the body's wound-healing response will cease to play its perverse role in perpetuating and complicating the lesion but will instead begin resolving and repairing the damage wrought in the artery wall. Under those conditions, the calcium deposits may well simply dissolve, or resolve as local cells are no longer being pushed (as they often are in atherosclerotic lesions) into adopting behaviors that closer resemble those of bone-forming cells.

Ultimately, barring strong evidence coming in one way or the other, the best policy is to remain agnostic about such cases, and focus precious research investments on those therapies that target the clearly-identified, recalcitrant cellular and molecular damage of aging. Like many types of secondary damage, other forms of tissue calcification may similarly become a non-issue once we've taken care of the core damage driving degenerative aging. If this turns out to be the case, calcification-specific rejuvenation biotechnologies will not be necessary.

Link: http://sens.org/research/research-blog/question-month-10-rejuvenation-calcification-amelioration

Researchers here report on another trial of embryonic stem cells, with a focus on demonstrating safety and absence of side-effects. The study size of four individuals, each given the treatment in one eye only, is too small to take the positive results as a sign that the treatment is effective enough to take to the clinic. The outcome is encouraging nonetheless:

Since their discovery and isolation in 1998, human embryonic stem cells (hESCs) have been considered a potentially valuable tool for generating replacement cells for therapeutic purposes. However, despite success in numerous animal models, fears over tumorigenicity and immunogenicity, coupled with ethical concerns, and inefficiencies in differentiation methods have all contributed to delays in carrying out human clinical trials. Only one group has reported the results of the safety and possible biological activity of embryonic stem cell progeny in individuals with any disease, but these investigators only enrolled patients who were mostly Caucasian. Here, we confirmed the potential safety and efficacy of hESC-derived cells in Asian patients.

Loss of the retinal pigment epithelium (RPE) is an important part of the disease process in several retinal disorders, including age-related macular degeneration (AMD) and Stargardt macular dystrophy (SMD). Animal studies have shown that hESC-derived RPE cell transplantation can rescue photoreceptors, resulting in the improvement of visual functions in RPE-oriented retinal degeneration models. Clinical trials of hESC-derived RPE cell transplantation have begun recently in the United States and Europe. Herein, we report on four Asian patients with macular degeneration (two with AMD and two with SMD) who underwent subretinal transplantation of hESC-derived RPE and were followed for 1 year to assess safety and tolerability.

In the two dry-AMD patients, visual acuity in the treated eyes improved by one letter (stable at counting fingers at 4 ft) and nine letters (a two-line improvement from 20/320 to 20/200) at 52 weeks, respectively. In contrast, the fellow (untreated) eyes decreased by 6 and 20 letters, respectively, during the same time period. In the two SMD patients, visual acuity improved in the treated eyes by 12 letters (counting fingers at 2 ft to 20/640) and 19 letters (a four-line improvement from 20/640 to 20/250), respectively, compared with nine letters of improvement in the fellow eyes at 52 weeks compared to baseline. The visual acuity improvement noted in the fellow eyes of SMD patients may be due to poorer baseline visual acuity than in the fellow eyes of the dry AMD patients. A 15-letter improvement (a doubling of the visual angle) is generally accepted as a clinically significant change.

Link: http://dx.doi.org/10.1016/j.stemcr.2015.04.005

Heterochromatin is the name given to the more tightly packed structural arrangement of chromosomal DNA in the cell nucleus. Changes in the way in which chromosomes are arranged within the cell nucleus are far from simple and, like various epigenetic modifications to DNA, have considerable influence over the pace of production of proteins. Circulating amounts of various proteins are the switches and dials of cellular machinery, changing constantly, determining behavior, and participating in countless feedback loops to further alter the production of other proteins. Every aspect of the cell plays a part in this dance, including the changing structural arrangement of nuclear DNA: it is characteristic of evolved complex systems that any given discrete part of the machine might be involved in a score of different important mechanisms.

It has been suspected for some time that heterochromatin has some influence on aging. Indeed, why shouldn't it? There are any number of ways to increase or shorten life span by altering levels of specific proteins in lower animals ranging from flies to mice. Alterations to the packing structure of DNA are likely to have many further effects, including changing levels of proteins known to alter the workings of longevity-associated processes. When researchers found a way to alter the proportion of DNA packed as heterochromatin in flies, they could dial up and dial down lifespan to a modest degree. There is considerable speculation as to why this works, but no definitive proof of the underlying mechanism as of yet. Sadly there is definitely an upper ceiling on the process: too much heterochromatin and the flies die.

Another interesting line of research links modifications to heterochromatin levels and cellular senescence. Increasing numbers of senescent cells with old age is well known to be a cause of degenerative aging, but here again the nature of the link with changing packaging of nuclear DNA is all very speculative. Much more research is needed to answer even the most basic of questions regarding how and why with any authority.

It is the case that researchers have used the so-called accelerated aging conditions of progeria and Werner syndrome, among others, to explore concepts and mechanisms that might be of relevance to normal aging. I say "so-called" because these conditions only have the superficial appearance of rapid aging: their underlying causes are in fact largely unrelated to ordinary aging. More than a decade after the identification of the critical breakage in cellular metabolism that causes progeria, for example, it is still far from clear whether this mechanism plays any meaningful role in human aging. It shows up to a small degree in old individuals, but is this significant over the present human life span? Perhaps not.

Here researchers investigating Werner syndrome make progress in understanding the disease mechanisms, which appear to involve heterochromatin. The publicity teams putting out the release are greatly overstating the relevance of this work to normal aging, however. Hype in research is a real problem, and sadly many groups who should know better are just as bad as the tabloids these days. So for my two cents, the relevance of this work on the causes of Werner syndrome to normal aging is just as speculative as is the case for work on the causes of progeria. It is likely that both conditions are the result of forms of damage that just don't happen to a meaningful level in a normal metabolism. When you are looking at broken biochemistry there is no guarantee that any of its operational characteristics are of use when understanding normal biochemistry, and breaking things to create a shorter life span usually has little relevance for any attempts to lengthen life span. Or at least that is the case until researchers can turn things around and demonstrate longer-lived animals via a reversal of the mechanism they are studying. Pay attention to longevity demonstrations, not demonstrations of shortened life spans.

Scientists discover key driver of human aging

Werner syndrome is a genetic disorder that causes people to age more rapidly than normal. People with the disorder suffer age-related diseases early in life, including cataracts, type 2 diabetes, hardening of the arteries, osteoporosis and cancer, and most die in their late 40s or early 50s. The disease is caused by a mutation to the Werner syndrome RecQ helicase-like gene, known as the WRN gene for short, which generates the WRN protein. Previous studies showed that the normal form of the protein is an enzyme that maintains the structure and integrity of a person's DNA. When the protein is mutated in Werner syndrome it disrupts the replication and repair of DNA and the expression of genes, which was thought to cause premature aging. However, it was unclear exactly how the mutated WRN protein disrupted these critical cellular processes.

Scientists sought to determine precisely how the mutated WRN protein causes so much cellular mayhem. To do this, they created a cellular model of Werner syndrome by using a cutting-edge gene-editing technology to delete WRN gene in human stem cells. This stem cell model of the disease gave the scientists the unprecedented ability to study rapidly aging cells in the laboratory. The resulting cells mimicked the genetic mutation seen in actual Werner syndrome patients, so the cells began to age more rapidly than normal. On closer examination, the scientists found that the deletion of the WRN gene also led to disruptions to the structure of heterochromatin, the tightly packed DNA found in a cell's nucleus. This points to an important role for the WRN protein in maintaining heterochromatin. And, indeed, in further experiments, scientists showed that the protein interacts directly with molecular structures known to stabilize heterochromatin - revealing a kind of smoking gun that, for the first time, directly links mutated WRN protein to heterochromatin destabilization.

"Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation. More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations - like remodeling an old house or car - to prevent, or even reverse, age-related declines and diseases."

A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

A fifty-year longitudinal study of human aging is wrapping up, and the results, as is usually the case, point to the importance of lifestyle choices in determining natural variations in human longevity. It also reinforces the point that you can't use good lifestyle choices to guarantee a path to an exceptional life span: the majority of people with the best lifestyles are still dead in their 80s, even though they on average do far better than their peers, with a lower level of pain and disease. The only way to reliably live far longer in good health is through progress in medical science, for the research community to produce rejuvenation therapies capable of repairing the cell and tissue damage that causes aging. The degree to which we all help to ensure those therapies are developed in time is the greatest determinant of our future health and longevity.

For the past 50 years, researchers have followed the health of 855 Gothenburg men born in 1913. Now that the study is being wrapped up, it turns out that ten of the subjects lived to 100 and conclusions can be drawn about the secrets of their longevity. Various surveys at the age of 54, 60, 65, 75, 80 and 100 permitted the researchers to consider the factors that appear to promote longevity. A total of 27% (232) of the original group lived to the age of 80 and 13% (111) to 90. All in all, 1.1% of the subjects made it to their 100th birthday. According to the study, 42% of deaths after the age of 80 were due to cardiovascular disease, 20% to infectious diseases, 8% to stroke, 8% to cancer, 6% to pneumonia and 16% to other causes. A total of 23% of the over-80 group were diagnosed with some type of dementia.

"The unique design has enabled us to identify the factors that influence survival after the age of 50. Our recommendation for people who aspire to centenarianism is to refrain from smoking, maintain healthy cholesterol levels and confine themselves to four cups of coffee a day." It also helps if you paid a high rent for a flat or owing a house at age 50 (indicating good socioeconomic standard), enjoy robust working capacity at a bicycle test when you are 54 and have a mother who lived for a long time. "Our findings that there is a correlation with maternal but not paternal longevity are fully consistent with a previous studies. Given that the same associations have been demonstrated in Hawaii, the genetic factor appears to be a strong one." But still we found that this "genetic factor" was weaker than the other factors. So factors that can be influenced are important for a long life.

Link: http://sahlgrenska.gu.se/english/research/news-article/lifestyle-advice-for-would-be-centenarians.cid1285361

A group of researchers are advocating for clinical trials in household dogs to test methods of gently slowing aging that so far are largely studied in mice only. The high level goal here is to produce more rigorous data in longer-lived mammals, something that is presently lacking. If as a side-effect it helps to raise awareness of the potential to extend healthy human life spans through progress in medical science, then all to the good. At this point the researchers have turned in part to the public and philanthropy to raise funds for the project, and are going about it in a fairly organized way. It is good to see the scientific community developing these skills, as this form of fundraising coupled with greater involvement of donors will become increasingly important in the future:

For millions of people, pets are considered part of the family. Unfortunately, companion animals such as dogs age rapidly and have relatively short life expectancies. Scientists want to change this. Research in the biology of aging has made tremendous strides over the past several years, with a few interventions found capable of slowing aging and extending lifespan in small mammals such as mice and rats. These same interventions could provide dogs with two to five or even more years of additional healthy, youthful life.

The Dog Aging Project is a unique opportunity to advance scientific discovery while simultaneously providing enormous benefit for people and their pets. We believe that enhancing the longevity and healthspan - the healthy period of life - in peoples' pets will have a major impact on our lives. To accomplish this goal, we are creating a network of pet owners, veterinarians, and scientific partners that will facilitate enrolling and monitoring pets in the Project. The Dog Aging Project has two major aims: a longitudinal study of aging in dogs and an intervention trial to prevent disease and extend healthy longevity in middle-aged dogs.

The first phase of this study will enroll middle-aged dogs (6-9 years depending on breed) in a short-term (3-6 month), low-dose rapamycin regimen and follow age-related parameters such as heart function, immune function, activity, body weight, and cognitive measures. These animals will then be followed throughout life to determine whether there are significant improvements in healthy aging and lifespan. The next phase of the study will enroll a second cohort of middle-aged dogs into a longer-term, low-dose rapamycin regimen designed to optimize lifespan extension. As with phase one, several age-related parameters will be assessed before, during, and after the treatment period. Based on the mouse studies, we anticipate that rapamycin could increase healthy lifespan of middle-aged dogs by 2-5 years or more.

We believe that improving healthy lifespan in pet dogs is a worthy goal in and of itself. To be clear, our goal is to extend the period of life in which dogs are healthy, not prolong the already difficult older years. Imagine what you could do with an additional two to five years with your beloved pet in the prime of his or her life. This is within our reach today, with your help.

Link: http://dogagingproject.com/