Why age? Why die? The answer today is because we have little choice in the matter. But what if we did have the choice tomorrow? The first real, working rejuvenation therapies, those based on clearance of senescent cells, are under active development in a growing number of companies. Pilot human trials have started at one non-profit, Betterhumans. Funds are flowing into this field of development as the evidence becomes ever more compelling. Adventurous individuals can even, with a little effort, obtain and use some of the early senolytic drug candidates for rational self-experimentation in destroying their own senescent cells. These compounds are not enormously expensive even now, prior to mass-manufacture. Given greater appreciation of this point, given more support, this and a range of other forms of human rejuvenation - approaches based on repair of the forms of cell and tissue damage that cause aging - could be moving much more rapidly towards the goal of reliable clinical treatments that are available to everyone at a reasonable cost.

Given the will to move forward, given popular support, we can give ourselves the choice of whether or not to age. Not quite tomorrow, but within a small number of years. Soon enough to matter. Soon enough that we should be thinking about it today, about how to help make this happen more rapidly, with greater quality of results, with fewer false starts. On this topic, the people behind the popular YouTube channels Kurzgesagt and GCP Grey, with some help from the volunteers of the Life Extension Advocacy Foundation, have put together a couple of videos that are attracting a fair amount of attention. Speaking as a generator of unrelenting walls of text, it is always a pleasure to see quality advocacy work carried out in other mediums. See what you think, and if you happen to know people who are primarily consumers of video rather than the written word, you might point them to these works.

Of the people who give the prospects for the defeat of aging a few moments of thought today, some few will go on to join and support our community tomorrow. Many hands make light work. We don't have to persuade the whole world, just enough people to fund the various necessary lines of rejuvenation research to the point at which they can be proven, picked up by the medical industry, and carried forward by the massive demand for health and working treatments for age-related disease. That is happening for senescent cell clearance, stem cell medicine, and some forms of amyloid clearance today, but there are many other areas that need as much success and attention, and it all needs to move more rapidly than is the case right now. We can do something about that, if we choose to.

Gamma-secretase inhibitors block the formation of the amyloid-β associated with Alzheimer's disease, but to date they are just one more in a long line of failed attempts to produce a therapy for that condition by adjusting the operation of cellular metabolism in the disease state in some way. Existing pharmaceutical gamma-secretase inhibitors act too generally, causing significant disruption of essential mechanisms that far outweighs whatever benefit they might produce. Here, however, researchers claim to have established a much more specific gamma-secretase inhibitor, one that only disrupts the formation of amyloid-β and nothing else. Is this good enough to justify another run at this challenge? Time will tell.

The most common neurodegenerative disorder, Alzheimer's disease is characterized by the buildup of amyloid plaques and neurofibrillary tangles in several brain regions. The leading hypothesis for its pathogenesis is the amyloid cascade - which suggests that the amyloid beta-protein, and particularly the amyloid-beta 42 peptide, initiates the disease process. An imbalance between the production and clearance of amyloid-beta results in the protein's aggregation into larger plaques that lead to the death of brain cells and the cognitive symptoms seen in Alzheimer patients. Several potential treatments have been developed that specifically target amyloid, but none have been effective in halting disease progression.

Amyloid-beta is produced by the cleavage of the larger amyloid precursor protein (APP) by an enzyme called gamma-secretase. Previous research led to the development of gamma-secretase inhibitors that totally block the function of the enzyme, but in clinical trials these drugs produced serious side effects through their effects on the processing of other proteins. As an alternative, researchers first developed the concept of gamma-secretase modulators (GSMs), which change but do not totally suppress the enzyme's activity, back in 2000. More recently reseearchers developed a group of soluble GSMs, one of which - SGSM-36 - appeared to be a promising candidate for clinical development.

In the current study, the researchers showed that three days of treatment with SGSM-36 reduced levels of amyloid-beta 42 in the brains and plasma of a validated mouse model of inherited Alzheimer's without affecting the processing of APP by other enzymes. In cellular models they compared the action of SGSM-36 to that of semagacestat, one of the gamma-secretase inhibitors that failed in clinical trials. While SGSM-36 treatment only reduced levels of the toxic amyloid-beta 40 and 42 peptides, semagacestat reduced all form of amyloid as well as gamma-secretase processing of other proteins, including the important signaling protein Notch, reduction of which may have caused the toxic effects of gamma-secretase inhibitor treatment.

"Genetic, biochemical, molecular biological and pathological evidence all support the hypothesis that excessive accumulation of amyloid-beta - particularly amyloid-beta 42 - is the primary event leading to Alzheimer's related pathology. In our future studies, we will be testing SGSM-36 against similar molecules that may have equal or higher potency in reducing amyloid-beta 42 and further investigating its molecular mechanisms in animal models, with the eventual goal of testing its potential in clinical trials."

Link: http://www.massgeneral.org/about/pressrelease.aspx?id=2161

Hematopoietic stem cells (HSCs), responsible for generating blood and immune cells, decline with age. This is one of the reasons why old immune systems suffer from a low rate of replacement of cells. For some years now, researchers have demonstrated that blocking Cdc42 reverses much of this decline, indicating that stem cell inactivity in the old is as much a matter of response to the aged, dysfunction tissue environment as it is a matter of intrinsic damage, at least in this population. Here, researchers review what is presently known on this topic.

Skin, intestine and blood are composed of short-lived cells that require continuous replenishment by somatic stem cells to maintain tissue homeostasis. Current theory is therefore that especially aging of stem cells that form these tissues will greatly contribute to the decline in tissue function with aging. Identifying mechanisms of stem cell aging and conditions under which aged stem cells become functionally similar to young stem cells might be important first steps towards devising treatments of aging-associated imbalance in tissue homeostasis and tissue regeneration with the ultimate goal of allowing for healthy aging.

Cdc42 belongs to the Rho GTPase family of the Ras superfamily, acting as a binary molecular switch that cycles between a GTP-bound active state and GDP-bound inactive state in response to a variety of extracellular stimuli. A key function of Cdc42 is regulation of elements that structure cells like the actin cytoskeleton or part of the microtubule network, which is believed to be a central mechanism for Cdc42-mediated cell polarization, adhesion and migration. Another important function of Cdc42 is to regulate cell growth signaling. It is becoming clear that the function and signaling pathways regulated by Cdc42 are tissue and cell type-specific, and the general principles of Cdc42 function defined by in vitro methods or from one tissue cell type may or may not apply to another cell type in in vivo situations. This also means that observations for example from fibroblasts (from which most of the information stems) might be informative for designing targeted experiments, but ultimately, in which pathway and function Cdc42 may operate in aged HSCs needs to be stringently dissected in HSCs and can not just be inferred from data obtained in other types of cells or systems.

Cell polarity is well characterized in epithelial cells and neuronal stem cells, but was only recently described to also exist in HSCs. Studies support a critical role of polarity in stem cell maintenance. What might be the role of polarity in stem cells? Polarity can be associated with specialized and compartmentalized functions in HSCs, with migration or with division. A defining feature of stem cells is their ability to maintain a balanced number of stem cells (self-renewal), while at the same time being able to generate specialized progeny (differentiation). Both processes depend on the ability of stem cells to undergo either symmetric or asymmetric divisions, which involve cell polarity.

Supporting a determining role for polarity in stem cell aging is a recent study showing that a loss of proper polarity in aged Drosophila germ-line stem cells correlates with their reduced function. To date, the role of HSC polarity with respect to the mode of HSC division and cell fate potential of daughter cells has not been experimentally tested. Given the established role of Cdc42 in mediating morphologic polarity in many cell types and in regulating HSC differentiation, it has been somewhat logical to postulate that Cdc42 plays a role in coordinating polarity in HSCs.

Genome-wide association studies of longevity in humans linked elevated expression of Cdc42 in hematopoietic cells to increased morbidity and aging. The holy grail of aging research is the question of rejuvenation. Are molecular mechanisms of aging reversible? If elevated Cdc42 activity is causally linked to stem cell aging and apolarity, then reversion of the level to the level found in young HSCs might result in "younger" HSCs. Aged HSCs, in which Cdc42 activity level was, via pharmacological inhibition, reduced to the level found in young mice, presented functionally and upon transplantation almost identically to young HCS. This suggests that Cdc42 activity might represent a novel target to rejuvenate aged HSCs via altering stem cell polarity.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427663/

There are great many people willing to rain fire and brimstone upon the merest mention of clinical studies in which the patient pays the costs. They emerge whenever any group runs such a study, or whenever an initiative earnestly proposes greater adoption of this structure of trial for medical procedures. At root, there is a sizable fraction of the population that seems very hostile to the idea that patients be allowed to choose their own risks, and we see this hostility whenever some loosening or adjustment of regulation is proposed. Petty authoritarianism, yes, but to the degree that it shuts down responsible experimentation and progress in medicine, and slows the pace of development as a consequence, it is just as harmful as the real thing.

A primary complaint about the patient paid structure is that it is impractical to conduct blind studies or use placebo treatments in a control group, as people tend to want to get what they paid for. This greatly reduces the ability of a study to assess the presence or absence of effects that are small, intermittent, or vary widely between patients due to as-yet unknown factors. If you are looking for small and unreliable effects, and sadly this is pretty much the case for most modern medicine for the treatment of age-related disease, then this is a fair criticism. You should not be trying to use this sort of trial structure in such a scenario.

However, when it comes to rejuvenation therapies we are not interested in small and unreliable effects. Small and unreliable is the same as failure. The SENS rejuvenation research programs, and any other initiative to repair the causes of aging, is aiming for large and reliable effects. The expectation is certainly there for success in addressing any of the molecular damage at the root of aging to produce reliably beneficial outcomes in patients. We all age for the same reasons, and a beneficial therapy in one individual should be beneficial in every individual of much the same age group. But people are used to the marginal effectiveness of present day medicine, the quest for tiny, incremental, unreliable gains, and that steers their expectations regarding the appropriate way to proceed.

When it comes to placebo treatments, it is arguably the case that some types of patient paid rejuvenation therapy trial could be structured to include them. Consider senolytic treaments that clear senescent cells, for example. One could envisage a trial that involves two treatments two weeks apart. One is a placebo. After each treatment, metrics are assessed. In mice, beneficial changes following elimination of senescent cells occur quite rapidly, as the senescence-associated secretory phenotype is cleared out. There will be measures of health status in humans that can be checked a few days or a few weeks later. So in general, there are often ways to proceed with a placebo for short-term studies and short-term measures.

Yes, for longer-term patient paid studies the use of a placebo control group just isn't practical. Again, however, the point of the exercise is the detection or confirmation of reliable, large effects. It is perfectly viable to use the rest of the population as your control group. If a senolytic therapy cuts back all sorts of measures of metabolic age quite quickly, to a degree that can only be achieved via other methods over a long period of time, if at all, then it is hard to reject that out of hand just because there was no control group of study participants. Based on the results in mice to date, and what is known of cellular senescence in humans, one would expect the first drug or other therapy to replicate the same degree of cell clearance in humans to be so very evidently beneficial that attempts to run blind studies with control group will be pointless - they will add little.

The response from the more conservative end of the scientific community following a patient paid study that shows significant benefits should be to pull in funds and interest to run their own more structured and careful studies to better quantify and improve upon the results. Publicity from the patient paid study will help them to do that, breaking through the reluctance that seems to characterize much of the industry. The patient paid structure is a way to bring in the necessary funding to carry out pilot studies in the absence of funding bodies within the existing institutions willing to do that. Given the history of the development of senescent cell clearance as a field of medicine - the long years in which it was ignored despite the compelling evidence, the struggle to fund the landmark studies in mice that proved that removing senescent cells could reverse aging - we should all be very skeptical that existing institutions will ever fund worthy projects in rejuvenation research if left to their own devices. They need to be kicked into action by outside efforts and outside funding, as they are otherwise happy to drift along performing marginal work.

If we want radical change to take place in the research community, if we want to see more work on human rejuvenation based on the SENS vision of repair therapies that can turn back aging, then patient paid studies are an important tool in the toolkit. Money doesn't grow on trees, and there are costs involved in getting the job done. Patient paid studies are one of the ways to overcome that hurdle.

Why pursue the development of rejuvenation therapies? What do I get out of it? The answer to that question - health! - is self-evident to those of us who have been thinking about this for a while, but a fair amount of advocacy for any cause is a matter of explaining what is obvious to the advocate, but not to someone unfamiliar with the idea. Sometimes it is hard to see one's own blind spots, and especially so when it comes to long exposure to a subject: we forget what it was like not to know. Given that, I think an overview of the point of developing rejuvenation therapies, discussing what an individual stands to gain, is a good thing to have in the toolkit.

I'm sure you've noticed that the Life Extension Advocacy Foundation has been shouting from the rooftops for quite a while that rejuvenation biotechnologies need to happen, and we're doing our best to make them happen as soon as possible. The job isn't easy; the fact that numerous people still raise concerns about the idea doesn't make it any easier, and we invest part of our time duly addressing those concerns. But the discussion about what might go wrong or how to prevent this or that hypothetical problem might draw attention away from another, possibly even more important question: why do we strive to make rejuvenation a reality? There's not much point in doing something if it yields no benefits, especially if that something requires as much hard work as this cause does; so, what are the expected benefits of rejuvenation?

Health: rejuvenation, we have said time and again, is pretty much all about health. The causal link between biological aging and pathologies is well established, and even when we account for the few elderly who are exceptionally healthy for their age, we're left with the obvious fact that the older you are, the sicker you are - and even the aforementioned exceptions aren't in the best of shape. To the best of my knowledge, the number of people who actively wish to be sick at some point tends to be fairly small; so, when you think that a truly comprehensive rejuvenation platform would allow people to maintain youthful health irrespective of their age, the health benefits of rejuvenation become crystal clear.

Independence: frailty, failing senses, weakness, and diseases aren't good friends of independence, but they are good friends of old age. That's why nursing homes exist in the first place - to take care of elderly people who are no longer independent. Again, even the few exceptional cases who manage on their own until death don't have it easy. Having people doing things for you can be nice in small doses, but having to have people doing things for you, not so much. Rejuvenation would eliminate the health issues that make the elderly dependent on others.

Longevity: as odd as it may sound, longevity is really just a 'side effect' of health, because you can't be healthy and dead. The longer you're healthy enough to be alive, the longer you'll live. Since rejuvenation would keep you in a state of youthful health, the obvious consequence is that you'd live longer. How much longer exactly is hard to say, but as long as you're healthy enough to enjoy life, it's safe to say that longevity would be a benefit; you'd have more time and energy to dedicate to what you love doing, and you could keep learning and growing as a person for an indefinitely long time.

Ultimately, all of these perks can be summarised into one: choice. If we had fully working rejuvenation therapies available and were thus able to keep ourselves always perfectly healthy, regardless of our age, we could choose whether we wanted to use these therapies or not. Those who wish a longer, healthier life could avail themselves of the opportunity and escape aging for as long as they wanted; those who prefer to age and bow out the traditional way could just as easily not use the therapies. Rejuvenation would give us an extra option we currently don't have; everyone is forced to face the burden of aging and eventually die of it, for the moment. Being able to choose what we wish for ourselves is one of the most fundamental human rights and an obvious, unquestionable benefit.

Link: https://www.leafscience.org/benefits-of-rejuvenation-biotechnology/

Mammalian heart tissue is not very regenerative in the normal course of events. The cells are slow to divide and make up their numbers, even in response to damage, whether that caused by a heart attack or other structural failure in aging tissues, or the more minor wear and tear of everyday life. Given this, one of the present themes in regenerative research is to find ways to spur greater rates of cell division in heart tissue, a compensatory strategy, but possibly beneficial enough to be worth trying. Approaches such as blocking the Hippo pathway, or delivering microRNAs that influence some of the same machinery look promising in animal studies. Here, researchers outline another approach to trigger the cell cycle and thus increase the pace at which heart cells divide, but with a focus on achieving this goal in transplanted cells rather than native cells.

Biomedical engineers report a significant advance in efforts to repair a damaged heart after a heart attack, using grafted heart-muscle cells to create a repair patch. The key was overexpressing a gene that activates the cell-cycle of the grafted muscle cells, so they grow and divide more than control grafted cells. Up to now, an extremely low amount of engraftment of cardiomyocytes has been a stumbling block in hopes to use grafted cells to repair hearts after a heart attack. Without the successful repair that a graft could potentially offer, the damaged heart is prone to later heart failure and patient death.

In experiments in a mouse model, researchers showed that gene overexpression of the cell-cycle activator CCND2 increased the proliferation of grafted cardiomyocytes. This led to increased remuscularization of the heart at the dead-tissue site of the heart attack, a larger graft size, improved cardiac function and decreased size of the dead tissue, or infarct. Besides regenerating muscle, the grafted cells also increased new blood vessel formation at the border zone of the infarct, apparently through increased activation of the paracrine mechanism. The team used cardiomyocytes that were derived from human induced pluripotent stem cells, as they work toward a goal of eventual clinical treatment for human heart attack patients.

Researchers first showed that overexpression of CCND2 in the human induced pluripotent stem cells-derived cardiomyocytes, or hiPSC-CMs, increased the proportion of cells that exhibited markers for the S and M phases of the cell-cycle, and for cytokinesis, as measured in cell culture. When they injected overexpressing hiPSC-CMs into the infarct region and the border of the infarct in the mouse model, the left ventricle ejection fraction was significantly greater at week four and the infarct size was significantly smaller, as compared with mice receiving normal hiPSC-CMs that did not overexpress CCND2. Both treatments were improvements as compared with untreated mice. Overexpression also led to an increased number of engrafted hiPSC-CMs, as measured by bioluminescence and human cell markers.

Link: http://www.uab.edu/news/innovation/item/8797-saving-hearts-after-a-heart-attack-overexpression-of-a-cell-cycle-activator-gene-enhances-repair-of-dead-heart-muscle

The immune system runs awry with age in a number of overlapping ways. The adaptive component of the immune system, made of B cell and T cell populations that adapt to store information about the pathogens they encounter, in particular suffers from forms of misconfiguration and exhaustion. Too many cells become devoted to useless tasks, such as the continually expanding and pointless battle against cytomegalovirus. Too much activity against pathogens produces large numbers of exhausted T cells and anergic T cells, incapable of responding aggressively when reacting to new threats, and not replaced rapidly enough with fresh T cells. Aging is accompanied by a diminished capacity to generate new T cells; this limit squeezes down from the top, while the failure and overspecialization of T cells squeezes up from the bottom. The immune system becomes ever less capable.

Because the T cell response to invaders involves replication, the rapid creation of a suitably equipped army to fight whatever the current war might be, there will always be some degree of cellular senescence in T cells, just as in all replicating cell types in the body. Cellular senescence is one of the full stops at the end of a normal cell's life span: it can only divide so many times before its telomeres become short, it hits the Hayflick limit, and either self-destructs or becomes senescent. Senescent cells near all go on to self-destruct a little later, or are destroyed by portions of the immune system dedicated to that purpose. Senescence can also be triggered by DNA damage resulting from a toxic environment, other forms of severe cellular stress, or the signals of nearby senescent cells. This serves to suppress the risk of cancer by removing those cells most likely to gain the combination of mutations needed to run amok. Senescent cells also have some transient, beneficial activities: they are involved in wound healing and embryonic development, again being destroyed after their task is complete.

Unfortunately some senescent cells linger for the long term, evading destruction. I say unfortunately because senescent cells generate a potent mix of inflammatory and other signals, the senescence-associated secretory phenotype (SASP). This disrupts regenerative processes, corrodes nearby tissue structures, and spurs the chronic inflammation that drives so many of the aspects of aging. While only a few percent of all cells have become senescent by the time old age rolls around, that is more than enough to have caused a significant fraction of the medical conditions of degenerative aging. Researchers have shown that senescent cells are one of the direct significant contributing causes of a wide range of issues: the ultimately lethal fibrosis that occurs in many organs; osteoarthritis; atherosclerosis; and more.

In the research noted here, the authors show that senescent T cells have essentially the same SASP as other forms of senescent cells investigated in recent years. This means that they will be just as harmful to health, a cause of aging given sufficient numbers. It is something of a debated question as to how much of T cell dysfunction with age is a matter of anergy, exhaustion, or senescence, and so also a question as to how many of these cells there are. If the numbers are significant, their presence also means that efforts to selectively remove senescent cells by provoking them into apoptosis, or by identifying their specific internal chemistry, should be expected to improve immune function alongside the other benefits shown to date in animal studies. Clearing out broken, dysfunctional T cells will free up space in the immune system and trigger their replacement. That will happen slowly in old people, given the limited replacement rate, but that too can be improved with suitable cell therapies - delivering large numbers of patient-matched immune cells is well within the present capacities of the biotechnology industry, just another of a fair number of potential treatments that have yet to be pushed through the regulatory system. Too many possibilities, too few researchers, and too high a regulatory barrier to entry.

Human CD8+ EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK

Immune senescence results from defects in T-cell immunity and is also characterized by a low-grade chronic inflammatory state. Little is known about the source of the inflammation that fuels most age-related diseases; however, it may derive from an age-related decline in homoeostatic immune function, resistance to endogenous microbes or senescent cells. The senescent phenotype is not just proliferative arrest; rather, it is a widespread change in protein expression and secretion, including pro-inflammatory cytokines, chemokines, growth factors and proteases, termed the senescence-associated secretory phenotype or SASP. Consequently, senescent cells can alter the tissue microenvironment and affect neighbouring cells through paracrine signalling.

The SASP was originally thought to result from persistent activation of the DNA damage response; however, it is now known to be regulated by p38 MAPK, which was shown to be both necessary and sufficient for its development in fibroblasts. The chronic and sustained activation of p38 MAPK differs substantially from the response to acute stress and was found to follow the kinetics of SASP development. Furthermore, siRNA interference of p38 MAPK was shown to significantly reduce the secreted levels of most SASP factors. To date, the SASP has predominantly been characterized in fibroblast cell culture models or aged mice, with very few reports of a SASP being found in the human immune system with either age or differentiation.

Senescent CD8+ T cells are found within the CD27-CD28- population, and these highly differentiated T cells can be further divided using CD45RA. T cells that re-express CD45RA within this subset have multiple characteristics of senescence, including a low proliferative activity, high levels of DNA damage and the loss of telomerase activity. We have also shown that p38 MAPK signalling, which is increased in highly differentiated CD8+ T cells, is involved in the loss of telomerase activity and proliferative capacity and that blockade of p38 MAPK activity with a specific small-molecule inhibitor can restore both proliferation and telomerase activity in these cells. However, surprisingly the CD45RA-re-expressing senescent T cells do not have critically short telomeres, suggesting that senescence in these cells may be induced by other mechanisms including DNA damage by increased reactive oxygen species production.

In this study, we demonstrate that irrespective of the derivation of CD8+ CD45RA+CD27- T cells, these primed cells exhibit a unique highly inflammatory secretory profile characteristic of the SASP, and we also provide evidence that ADAM28 can be used as a functional marker of senescence in CD8+ T cells. Furthermore, we show that the secretory phenotype in CD8+ CD45RA+CD27- T cells is controlled through p38 MAPK signalling, which contributes to age-associated inflammation.

There are any number of specific proteins associated with the progression of aging and its dysfunctions in one way or another. The overwhelming majority are not directly involved in the fundamental molecular damage that causes aging, but rather in the secondary consequences and reactions to that damage. It is therefore the case that they are poor targets for efforts to treat aging, because trying to manipulate the dysfunctional state of metabolism is a poor substitute for fixing the root cause damage that leads to that dysfunction. The research here is an example of the type, and the sort of investigations that result.

The maintenance of cellular and organismal homeostasis determines the progress of aging. On a cellular level, homeostasis is maintained, in part, through macroautophagy (hereafter referred to as autophagy), a conserved mechanism by which a cell achieves multiple goals, including clearance of misfolded proteins and organelle turnover with subsequent recycling of degraded constituents. As cells age, their ability to perform these functions declines. This likely leads to an unsustainable accumulation of protein aggregates, which ultimately present an obstacle to cellular survival. Indeed, studies of the distinct signaling networks in C. elegans that modulate lifespan have provided evidence of a central role for autophagy in many known longevity paradigms.

Thus loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans, and also modulate mammalian vascular age-associated phenotypes.

Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models. Conversely, Kruppel-like family of transcription factor overexpression extends nematode lifespan in an autophagy-dependent manner. Furthermore, we show the mammalian vascular factor Kruppel-like family of transcription factor 4 (KLF4) functions to regulate autophagy in vascular endothelial cells and modulate blood vessel aging in mice. KLF4 expression also decreases with age in human vascular endothelium. Thus, Kruppel-like family of transcription factors constitute a transcriptional regulatory point for the modulation of autophagy and longevity in C. elegans with conserved effects in the murine vasculature and potential implications for mammalian vascular aging.

Link: https://doi.org/10.1038/s41467-017-00899-5

In parabiosis studies, a young and old animal have their circulatory systems linked. This is shown to improve measures of aging in the old animal, such as regenerative capacity, stem cell activity, and so forth. There is considerable debate over the mechanisms involved, with the current balance of evidence favoring a dilution of harmful factors and signals present in old blood and tissues rather than a delivery of beneficial factors and signals present in young blood.

In the research reported here, the authors examine the effects of parabiosis on the function of aged kidneys. It is too early to say what this will add to the discussion of specific mechanisms, but speculation is certainly possible. Even given the consensus, it has to be said that the data looks a lot one might expect to see if young immune cells are coming in and doing a better job of reducing the senescent cell burden in an aged kidney than the native, old immune system is capable of achieving. Yet it is also possible that simply altering the balance of factors in the surrounding environment spurs more of these unwanted and harmful cells to self-destruct on their own, given that they are already primed for apoptosis.

Whether changes in internal body environment affect kidney aging remains unclear. Specifically, it is unknown whether transplanted kidneys from older donors recover from tissue damage after placement in younger recipients. In this study, a parabiosis animal model was established to investigate the effects of a young internal body environment on aged kidneys.

The animals were divided into six groups: young (Ycon) and old (Ocon) control groups, isochronic youth-youth group (Y-IP), elderly-elderly group (O-IP) and heterochronic youth (Y-HP) elderly (O-HP) group. After parabiosis, tubule and interstitial tissue scores in the O-HP group were significantly lower than in the Ocon and O-IP groups. The expression of aging-related protein p16 and senescence-associated β-galactosidase in the O-HP group was significantly reduced compared with the Ocon and O-IP groups. Autophagy factor Atg5 and LC3BII were significantly upregulated, while the expression of the autophagic degradation marker (P62) was significantly downregulated in the O-HP group compared with the Ocon and O-IP groups.

With the same comparison, the positive cells of TUNEL staining and the expression of inflammatory cytokines IL-6 and IL-1β were significantly reduced, while the total/cleaved caspase-3 and total/pNF-κB were significantly increased in the O-HP group. The results demonstrated that a young blood environment significantly reduces kidney aging. These findings provide new evidence supporting an increase in the upper age limit for human kidney transplantation donors.

Link: https://doi.org/10.1093/gerona/glx183

At least one group is running trials of stem cell transplants as a potential treatment for age-related frailty syndrome: the scope of the possible in the near term is to find way to incrementally improve the condition, not produce a sizable reversal, but that is an improvement over the current situation, given that there is no effective treatment. The closest thing to a standardized, proven, reliable class of stem cell therapies involves the use of mesenchymal stem cells, sourced from a patient, or from lines of cells grown and engineered for transplantation with minimal risk. The primary outcome of mesenchymal stem cell therapies, or at least the reliable outcome, is a reduction in the systemic, chronic inflammation that accompanies old age. While it is entirely possible that other mechanisms are at work, the cells typically don't last long following transplantation, and thus it is the brief signaling changes that must produce benefits that can last for months or longer.

Chronic inflammation is a major problem in aging. It drives progression of most of the age-related conditions, and high levels of inflammation are certainly considered to be a major component of frailty syndrome in the old. In the context of a general treatment for frailty based on reductions in inflammation, the focus is less on the acceleration of specific age-related conditions over time, however, and more on the immediate consequences of constant high levels of inflammation for cell biochemistry, pain, cognitive function, joint function, regeneration, and tissue maintenance. Many aspects of age-related dysfunction are to some degree being actively maintained in their current impacted state by the presence of inflammation - take away that inflammation, and the problems subside a little, back to the lower level of harm and loss expected due to accumulated cell and tissue damage.

In recent years, it has become clear that chronic inflammation, as opposed to the normal short-term inflammation resulting from injury or infection, disrupts the finely tuned dance carried out between tissue and immune system needed for regeneration. This is an emerging theme in the investigation of how senescent cells cause aging, for example, as these unwanted cells are potent sources of inflammatory signaling. So if we see unreliable or marginal benefits from stem cell therapies that look like enhanced regeneration, it might well be that this is at root a short-term reduction in the age-related disruption of tissue maintenance - perhaps enough to allow a little reconstruction to take place in some patients. This is speculation, of course, and the cellular biochemistry is challenging to investigate; we should probably expect a first generation of moderately reliable therapies in advance of complete understanding of their mechanisms. Here is another point to consider on this topic: if the inflammation model of benefits is correct, then clearance of senescent cells should be at least as good a treatment for frailty as mesenchymal stem cell transplant, and probably better and more lasting.

Stem Cell Transplantation for Frailty

It was reported over 50 years ago that old age is associated with depletion and loss of function of stem cells. Since that time, there has been extensive research confirming the deleterious effects of aging on all types of stem cells, and a growing belief that such age-related changes in stem cells further accelerate tissue and organismal aging. There have also been hundreds of early-phase clinical trials using mesenchymal stem cells (MSCs) for a wide range of disorders including graft-versus-host disease, autoimmune disease, and heart disease where both regenerative and immunomodulatory effects of MSC are harnessed.

The possibility that stem cells might be "vehicles for youthful regeneration of aged tissues" has been well recognized. Mesenchymal stem cells from young mice infused into old mice improved age-related osteoporosis and also increased life span. Transplantation of stem cells from young mice to old mice has also been reported to improve cardiac and reproductive function. There is clearly an opportunity to now undertake clinical trials to explore the therapeutic potential for stem cell transplants for age-related conditions in older humans.

Frailty provides an ideal target for clinical trials of MSC transplantation and aging. Frailty in older humans is associated with reduced circulating MSC, while many of the clinical features of frailty involve mesenchymal tissues, that is, the musculoskeletal system. In clinical practice, the diagnosis is often made based on clinical impression rather than any formal diagnostic process. The definitions of frailty overlap with definitions of aging and sarcopenia. Frailty can be considered to be the end-stage consequence of the biological processes of aging and accumulated chronic disease. Recently two clinical trials were published on the effects of MSC transplantation in frail older humans, and these trials represent potential landmarks in the treatment of frailty. Both studies are early-phase trials of a small number of participants, designed primarily to assess safety, so conclusions about efficacy need to be treated with caution. Even so, the results are striking and, at minimum, pave the way for large randomized Phase III clinical trials.

The first study was a Phase I open-label trial where allogeneic MSC collected from the bone marrow of younger donors aged 20-45 years were used to treat 15 frail patients (average age 78 years) using a single infusion of either 50, 100, or 200 million cells. After 6 months, outcomes that improved included the 6-minute walk and tumor necrosis factor α (TNFα) levels, with variable improvements in forced expiratory volume in 1 second (FEV1), Mini-Mental State Examination (MMSE), and quality of life. No significant adverse effects were recorded, and only one patient developed antibodies that could potentially neutralize the outcomes.

The second study by the same group was a Phase II randomized, double-blinded trial of allogeneic MSC at two doses (100 or 200 million cells) versus placebo. The participants were 30 frail patients with an average age of 76 years. No therapy-related adverse effects were documented at 1 month. Improvements were reported for physical performance, the 6-minute walk test, short physical performance exam, FEV1, and TNFα mostly in the 100 million cell groups. The authors conclude that the treated groups had "remarkable improvements" in outcomes. There are always caveats associated with interpreting efficacy in small numbers of subjects, yet it is remarkable that a single treatment seems to have generated improvement in key features of frailty that are sustained for many months.

Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty

The purpose of this Phase 1 pilot study, AllogeneiC Human Mesenchymal Stem Cell in Patients with Aging FRailTy via IntravenoUS Delivery (CRATUS), was to evaluate the safety and tolerability of allogeneic hMSCs (allo-hMSCs) in patients with aging frailty and to explore domains of treatment efficacy of allo-hMSCs through the reduction of signs and symptoms of aging frailty. The major new findings of CRATUS are that intravenous allo-hMSC infusions are safe and well tolerated in elderly individuals with early signs and symptoms of frailty. Importantly, there were improvements in a constellation of parameters that are important predictors of morbidity and mortality in patients with aging frailty.

With no current standard of care for frailty, allo-hMSCs may hold great promise as a cell therapy agent for patients with this syndrome. The underlying basis for positive effects of allo-MSCs are likely due, at least in part, to anti-inflammatory and proregenerative effects. In this regard, frailty is characterized by systemic inflammation and low "reserve capacity" of organ systems thought due to diminished endogenous stem cell production. Replenishment of the body's stem cell "factory" and/or revitalization of stem cell niches via intravenous infusion of allo-hMSCs may help treat the morbidities associated with aging frailty.

Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial

There are no specific medical or biologic treatments that ameliorate or reverse frailty. Stem cell depletion is a key mechanism postulated to contribute to frailty. In this regard, we recently conducted a phase I open label study of human allogeneic mesenchymal stem cells (allo-hMSCs) intravenously infused for frailty, which showed that the cells could be safely administered, improved measures of functional capacity, and reduced inflammation. Therefore, we conducted the current phase II double-blinded and placebo-controlled study in order to test the hypothesis that exogenous allo-hMSCs could reverse signs and symptoms of frailty in older individuals.

Similar approaches have been shown to exert beneficial effects on the cardiovascular system, with functional improvements on various types of heart disease, endothelial function, and systemic inflammation. Given their pleiotropic mechanisms of action, which include antifibrotic, anti-inflammatory, proangiogenic properties, and their ability to stimulate endogenous progenitor cells, we hypothesize that their use may offer a novel treatment strategy in frail patients.

The findings here replicate in large part the results of the earlier open label study, support the concept that MSCs have bioactivity against aging frailty, and confirm the fact that 100 million cells represents a superior dose level compared to 200 million. The reasons underlying the inverse dose relationship noted here remain incompletely understood. The 100 million dose group produced significant improvements in both physiologic and immunologic markers of frailty, while the high dose group solely demonstrated positive immunomodulatory effects.

Near the entire corpus of present day medicine for age-related disease, even the comparatively successful treatments, is essentially compensatory in nature. It fails to address in any meaningful way the underlying causes of aging and disease. "Comparatively successful" is presently measured against doing nothing, rather than against the goal of a cure, of controlling the aging process. By that latter standard, there is no such thing as successful medicine for age-related disease. Yet.

The research noted here is one small demonstration of the point that compensatory efforts fail because they do not address the root causes of the problem: the underlying pathology marches on, overwhelms the bounds of possible compensatory efforts, and patients decline and die as a result. Blood pressure rises with age because blood vessels stiffen, because of persistent cross-links in the extracellular matrix, and because of calcification encouraged by the presence of senescent cells, and because of related dysfunctions in the signaling mechanisms that coordinate vascular contractions and reactions to pressure. Current pharmaceuticals that do reliably lower blood pressure do nothing for the roots of the issue.

Hypertension affects about 40% of those aged over 25 and is a major risk factor for heart disease, stroke and kidney failure. An interdisciplinary group of scientists found that conventional medication aimed at reducing high blood pressure restored normal vascular rhythms only in the largest blood vessels but not the smallest ones. "It is clear that current anti-hypertensive treatments, while successfully controlling blood pressure, do not restore microvascular function."

Based on a networks physiology approach, the researchers compared a group aged in their twenties and two older groups aged around 70 - one with no history of hypertension and the other taking medications for high blood pressure. In the older group being treated for high blood pressure the drug treatment restored normal function at the level of arterioles and larger vessels. But when the researchers studied the nonlinear dynamical properties of the smallest blood vessels in the body, they found differences between the two older groups.

"Specifically, current hypertensive treatment did not fully restore the coherence or the strength of coupling between oscillations in the heart rate, respiration, and vascular rhythms (vasomotion). These are thought to be important in the efficient and adaptive behaviour of the cardiovascular system. Indeed, one aspect of ageing is the progressive physiological weakening of these links that keep the cardiovascular system reactive and functional. The results have not only confirmed previous observations of progressive impairment with age of the underlying mechanisms of coordination between cardiac and microvascular activity, but for the first time have revealed that these effects are exacerbated in hypertension. Current antihypertensive treatment is evidently unable to correct this dysfunction."

Link: http://www.lancaster.ac.uk/news/articles/2017/blood-pressure-medication-does-not-completely-restore-vascular-function-/

Models and trends established across collections of species are used as a tool to try to understand the complex relationship between metabolism and aging, meaning how exactly the natural variations between individuals and species arise from the behavior of cells and interaction with the surrounding environment. This is something of a sideshow to the main business of rejuvenation research, but since the scientific impulse is to map and understand, there is much more of the sideshow taking place than actual efforts to repair the causes of aging. In this slow and expensive business of deciphering the detailed progression of aging, the greatest insight can arise from the outlying examples that do not fit into the models and hypotheses that manage to explain most observations. Some of the various long-lived mole-rat species provide good examples of the type, as illustrated by this open access paper.

Reproduction is an energetically expensive process that supposedly impairs somatic integrity in the long term, because resources are limited and have to be allocated between reproduction and somatic maintenance, as predicted by the life history trade-off model. The consequence of reduced investment in somatic maintenance is a gradual deterioration of function, i.e. senescence. However, this classical trade-off model gets challenged by an increasing number of contradicting studies that show no negative effect of high metabolic rate on lifespan, or even a positive association. Consequently, more research is needed to gather representative data from animals with different life histories, to gain a comprehensive understanding of how life history trade-offs influence lifespan.

Ansell's mole-rats (Fukomys anselli) are subterranean rodents with an extraordinary long lifespan, 22 years being the maximum recorded age thus far. They live in multigenerational families where typically only the founder pair (breeders) reproduces. Most of the offspring (non-breeders) forego reproduction and remain in the natal family. A clear contradiction to the classic trade-off model has been shown in this species: breeding individuals live up to twice as long as their non-breeding counterparts, a feature which is unique amongst mammals. Previous studies showed that daily activity between breeders and non-breeders does not show differences, and social rank does not influence life expectancy. Hence, extrinsic factors like aggression, fighting and higher workload in non-breeders are not likely to influence the lifespan difference. Here, we test the hypothesis that breeders and non-breeders of Ansell's mole-rats differ in their mass specific resting metabolic rate (msRMR), as a possible approach to understand the bimodal aging pattern.

Low msRMR is a common trait in bathyergid rodents interpreted as an adaptation to the subterranean habitat, and our measurements generally confirm previous studies. However, our finding that long-lived breeders of F. anselli have higher metabolic rates compared to shorter-lived non-breeders is novel. This aspect is most interesting since investment in reproduction was long thought to impair somatic maintenance according to the classical trade-off model, but recent findings refer to the trade-off model as being too simplistic. Especially in terms of female reproduction, a meta-analysis from different homeothermic vertebrates has shown that in intraspecific comparisons between breeders and non-breeders, breeders had lower levels of oxidative damage in certain tissues.

This effect could be attributed to upregulation of antioxidant defense mechanisms, such as glutathione or superoxide dismutase activity, which shows a tissue-dependent upregulation in several species during reproduction. This oxidative shielding hypothesis, even if not consistent across different studies, suggests a reproduction-induced protection of mothers and offspring. Ansell's mole-rats are continuously reproducing once they achieve the reproductive status. Oxidative shielding might protect the animals from detrimental pregnancy effects due to a higher energy turnover in female breeders compared to non-breeders. However, the bimodal lifespan in Ansell's mole-rats is not sex-dependent, indicating a general effect in terms of reproductive status, msRMR, and lifespan rather than just a pregnancy effect restricted to females.

Oxidative stress as a main factor contributing to life history trade-offs is getting challenged by increasing contradictory studies. The uncoupling-to-survive hypothesis complements simplistic theories of senescence by explaining apparent exceptions. It suggests that elevated oxygen consumption, a measure for msRMR in the present study, could be also observed due to uncoupling of proton flux in the mitochondria. This process, also referred to as inducible proton-leak, is facilitated by uncoupling proteins and increases RMR. On the other hand, inducible proton-leak is known to reduce ROS production by reducing mitochondrial membrane potentials. Hence the higher msRMR measured in breeders of Ansell's mole-rats could be due to higher rates of mitochondrial uncoupling compared to non-breeders.

Several studies found higher rates of uncoupling in those laboratory mice that lived longer compared to other individuals with shorter lifespans. However, in the case of mole-rats this model should be considered carefully, since in naked mole-rats, surprisingly high levels of oxidative damage to DNA, lipids and proteins were found, which contrasts with the proposed benefit of mitochondrial uncoupling. In general, our finding stresses the complexity of currently discussed aging mechanisms.

Link: https://doi.org/10.1186/s12983-017-0229-6

This year's SENS Research Foundation winter fundraiser launches today, with a target of $250,000. Donations will support ongoing rejuvenation research programs at the SENS Research Foundation Research Center, as well as in laboratories at Yale, the Buck Institute, the Babraham Institute, and Oxford. The SENS Research Foundation continues to carefully unblock important but neglected fields of research that are relevant to repairing the cell and tissue damage that causes aging - you might take a look at the SENS timeline to see the past and presently ongoing success stories, in which charitable donations were used to move promising research from idea to demonstration to commercial development. A range of important research programs are still in the early stages or the middle of this process, and thus the more that we support these efforts, the faster the progress towards a comprehensive suite of rejuvenation therapies capable of turning back aging and age-related disease.

Following last year's model, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! have put together a $36,000 challenge fund for SENS Patrons. We will match the next year of donations for anyone who becomes a SENS Patron by signing up as a new monthly donor at the SENS Research Foundation between now and December 31st of this year. I invite you all to please put your best foot forward and help out. The SENS Research Foundation is a 501(c)(3) charity, and donations are tax deductible, even in much of Europe, though the details are a little more complex, and vary by country. Tell a friend. Print out and put up one of our posters. Set up a fundraising exercise of your own - there are many ways to help out.

I might be just a touch biased on this topic, but to my eyes supporting this cause is truly effective altruism. Not just because aging is the greatest cause of pain, suffering, and death in the world - by a large margin, and the poor suffer the most, as is always the case - but because the SENS Research Foundation, and the Methuselah Foundation before it, have a proven track record when it comes to turning philanthropic donations for SENS research programs into concrete progress towards human rejuvenation.

Past charitable donors have seen a number of strategic investments in promising but underfunded research turn their donations into active commercial development efforts. For example: work on preventing the consequences of mitochondrial DNA damage, one of the root causes of aging, through allotopic expression of mitochondrial genes was funded with modest support starting back in 2008. That gave rise to Gensight, a company that now puts tens of millions of dollars into developing this technology. SENS programs that mined bacteria for enzymes capable of safely breaking down age-related metabolic waste have resulted in candidates for drug development that are licensed out to the LysoClear program to tackle age-related macular degeneration, and to human.bio for efforts to break down some of the harmful compounds that contribute to atherosclerosis. Further, efforts to remove the transthyretin amyloid connected to heart disease, using catalytic antibodies, have moved into a company for commercial development. More is on the way. This year, work on an important component of a universal cancer therapy, achieved through suppression of telomere lengthening, is being spun out, along with promising work on glucosepane cross-link breaking - one of the more important causes of the loss of tissue elasticity that damages skin and, more importantly, blood vessels.

The SENS Research Foundation has also funded research in cellular senescence in aging, and SENS advocates has persistently and actively fought for more funding for this line of development for fifteen years. This helped to bring to an end the long period during which the research community rejected this very important field of research. As senolytic therapies to clear senescent cells have finally blossomed into a suddenly popular area of development, the SENS Research Foundation helped to seed fund the startup Oisin Biotechnologies, working on a gene therapy approach to selectively destroy senescent cells and cancerous cells with minimal side-effects. That company is presently raising a new round of funding to take their work to the clinic.

As a final item to consider, remember that all of this exciting progress towards the end goal of effective human rejuvenation was built atop a modest starting point, that being the small, simple decisions of a few thousand people just like you and I: people who gave a small amount of money every month, such as the members of the Methuselah 300. It is because of these people, their conversations, and their dedication and vision, that the first SENS rejuvenation research programs took place at all. It is because of these people that high net worth individuals such as Peter Thiel, Michael Greve, and Jim Mellon have been drawn to the field to provide significant material support. We make a difference. We are the leaders, we are the people carrying the lantern to light the way. Because of our efforts, the world will be a better place tomorrow, one in which being old doesn't have to mean being sick, frail, and faltering.

It has been observed that Alzheimer's disease and osteoporosis appear to be correlated to a larger degree than one would expect simply because both emerge, after a long chain of cause and effect, from the root causes of aging. That they are correlated in this way suggests that they share in common some parts of the middle of that long chain. Given that osteoporosis is a condition of the bones, a disruption of the balance between cells that create bone and cells that destroy bone, and Alzheimer's is a condition of the brain, in which aggregated proteins overwhelm cells, what could these two very different outcomes of aging have in common? This open access paper looks at some of the current evidence and hypotheses.

Accumulation of abnormally folded amyloid beta peptide (Aβ) in cerebral amyloid plaques is the pathologic hallmark of Alzheimer's disease (AD). Aβ originates from the amyloid precursor protein (APP), a membrane protein expressed in many tissues and synapses of neurons with unknown function. A group of specific enzymes named secretases cleave APP into distinct fragments. APP cleavage by β-secretase and then γ-secretase leads to pathological Aβ oligomers. Oligomers are the units which form protofibrils and later fibrils and plaques. Genetic models of AD are typically established by excessively expressing Aβ protein and the current hypothesis of AD etiology centers around amyloid plaques.

Unlike the complexity and controversy in AD, the pathogenesis of osteoporosis is known as an imbalance between bone formation and mineralization. Hyperparathyroidism, Vitamin D deficiency, and steroid use are common causes of osteoporosis. Osteoporosis is mostly asymptomatic until minor trauma or falls lead to fractures. Bone formation involves bone matrix production and mineralization, whereas bone resorption is a biological erosive process mediated by osteoclasts. When the balance leans toward bone resorption, bone mineral density (BMD) decreases and osteoporosis develops.

Bone resorption is driven by the receptor activator nuclear factor-kappa B ligand (RANKL) / receptor activator nuclear factor-kappa B (RANK) signaling network, a signaling complex with multiple downstream pathways. The binding of RANKL to RANK triggers the cascade. Amyloid deposition in the brain and RANKL signaling are two seemingly independent pathways leading to AD and osteoporosis. The possible linkage between these two pathways has been investigated by measuring osteoclast activities in a transgenic mice model of AD. Both in vitro and in vivo examinations showed enhanced Aβ expression in bone, together with increased adipose tissue formation in the marrow space, analogous to osteoporotic bones. The abnormally expressed amyloid deposition appears to interfere with the RANKL signaling cascade and in turn the balance between bone formation and bone resorption. Similar findings extend to human studies.

Previous observational studies have reported the increased frequency of comorbid osteoporosis in AD. The relationship between these two diseases is more likely one of shared etiology than one condition causing the other. The overexpression of Aβ may take place in both brain and bone, interfering with the RANKL signaling cascade, enhancing osteoclast activities, and leading to osteoporosis. There is a growing body of evidence from in vitro and in vivo studies that the AD pathology in the brain can be reflected by examining the bone. Future investigation will focus on assessing biomarkers of cognitive aging in patients with osteoporosis and looking into the bone microstructure of patients with AD.

Link: https://doi.org/10.4103/tcmj.tcmj_54_17

Calorie restriction slows aging, with the current consensus being that this is largely mediated through increased autophagy, the housekeeping processes that clear out and recycle broken components within the cell. Calorie restriction does, however, change more or less everything there is to be measured in cellular metabolism, so it is certainly possible that other mechanisms are relevant. In this context, researchers here present evidence to show that, at least in flies, the defense against infection mounted by the innate immune system is enhanced by short term calorie restriction. It is also worth considering that this sort of effect may explain some of the degree to which calorie restriction reduces the burden of cellular senescence and cancer risk over the long term, by incrementally improving the ability of the immune system to remove harmful and potentially harmful cells.

Studies of dietary restriction, a reduction in nutrient intake without malnutrition, in a diverse array of organisms have revealed it to be an effective way to extend lifespan and promote broad-spectrum improvement in health during aging. Early work focused on total caloric intake as the driving force behind these beneficial effects, but studies that have comprehensively examined the effects of individual macronutrients on lifespan underscore the importance of protein-to-carbohydrate ratio. In the fruit fly, Drosophila melanogaster, yeast restriction has been used as an alternative to wholesale dilution of the diet to effectively extend female fly lifespan. These effects have also been observed in mammals, where protein restriction increased rodent lifespan. Together, these studies establish that the life-extending benefits associated with dietary restriction can be achieved without reducing total caloric intake when the relative consumption of protein to carbohydrates is low.

A striking feature of the effects of dietary restriction is its acute nature, yielding beneficial outcomes with short-term application. In Drosophila, a switch to a restricted diet reduced short-term mortality risk within 48 hr, and in mice, 1 week of protein starvation decreased tissue damage caused by temporary blockage of blood flow during surgical operation, greatly improving survival following renal ischemic injury. Even ad libitum feeding of low-protein, high-carbohydrate diets for 8 weeks resulted in metabolic improvement in mice compared to those fed high-protein, low-carbohydrate diets.

A significant threat to global health is infectious diseases. Acute preventative strategies that strengthen immunity prior to such procedures are therefore of strong interest. To answer the questions of whether, similar to general health and aging, innate immune function is acutely modulated by individual nutrients, we executed a comprehensive analysis of the effects of dietary composition on survival following pathogenic infection in Drosophila. Although lacking adaptive immunity, insects are equipped with innate immunity, which is an ancient first-line defense mechanism that recognizes the pattern of invading microorganisms as well as their virulence factors. Drosophila innate immunity has humoral and cellular components, and this innate immune response is highly conserved between Drosophila and mammals.

Here, we present evidence that yeast restriction, but not carbohydrate restriction, substantially improves fly survival following bacterial infection through several components of innate immunity. We find that yeast-restriction-mediated enhancement of innate immunity is orchestrated by components of the target of rapamycin (TOR) signaling network, in which reduced TOR signaling results in a stabilization of the transcription factor Myc through its suppressor protein phosphatase 2A. Myc in turn mediates a sustained induction of genes that encode antimicrobial peptides, which are effective bacterial killers. These results implicate a function for protein phosphatase 2A (PP2A) and Myc as signaling molecules that serve to potentiate the immune response in yeast-restricted animals following pathogenic infection.

Link: https://doi.org/10.1016/j.celrep.2017.06.052