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A Study Observing No Significant Relationship Between Exceptional Longevity and Cardiovascular Risk Factors

A Study Observing No Significant Relationship Between Exceptional Longevity and Cardiovascular Risk Factors

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Today’s open access paper illustrates one of the many issues inherent in the study of the biochemistry and genetics of exceptionally long-lived people, which is that the data from various different initiatives rarely agrees. The effects of individual or even groups of gene variants are small and hard to pin down. Past studies have suggested that exceptional longevity is correlated with a lack of cardiovascular risk factors, whether genetic or measured aspects of biochemistry such as lipid levels in blood. That seems a sensible hypothesis: cardiovascular disease removes people from the population, therefore older cohorts should exhibit fewer signs of risk for cardiovascular disease. Yet that is not the case in the work presented here: there is no good association between longevity and lesser presence of risk factors.

What this sort of distribution of results should tell us is that the biochemistry of exceptional human longevity is a poor area of study if the goal is to produce reliable therapies with large effects on human aging. Old people who survive to very late life do so largely because they are either lucky (in exposure to pathogens, in the way in which the damage of aging progressed in a stochastic manner in their case) or because they made good lifestyle choices for much of their span of years. Or both. Beneficial genetic variants and consequent differences in cellular metabolism appear to confer only very modest increases in the odds of living for a long time, and even for those people who do live longer, the impact of degenerative aging is very significant. An environment of small, unreliable effects should be skipped in favor of research strategies with larger potential gains at the end of the day.

Exceptional Longevity and Polygenic Risk for Cardiovascular Health


Exceptional longevity, defined as exceeding the average life expectancy, is multifaceted with genetic, environmental, and epigenetic factors all playing a role. Exceptionally long-lived (ELL) individuals are examples of successful ageing with a proportion demonstrating compression of morbidity. It is important to study these models of successful ageing, as these rare individuals may reveal novel longevity-associated pathways, which may ultimately translate into strategies to promote health in our ageing population.

There is evidence linking healthier cardiovascular risk profiles and lower incidence of cardiovascular disease with longevity. Analysis of lipid metabolism in longevous families identified changes in lipid concentration in the offspring of nonagenarians. Levels of apolipoproteins, important lipid transporters in the circulatory system, have been observed to decline with age. However, higher apolipoprotein levels in the exceptionally long lived have been reported, suggesting a younger apolipoprotein profile that may promote longevity.

Polygenic risk scores (PRS) for cardiovascular-related phenotypes can now be calculated due to the availability of summary data from genome-wide association studies (GWAS) examining a broad range of traits from lipids to coronary artery disease. This facilitates the evaluation of the contribution of polygenic risk for cardiovascular risk factors and disease to exceptional longevity and successful ageing. Thus, the purpose of this study was to explore the genetic profiles of ELL individuals aged (≥95 years) by assessing their polygenic risk for cardiovascular related risk and disease phenotypes relative to middle-aged controls.

This study did not confirm the hypothesis that ELL individuals have lower polygenic risk scores for cardiovascular-related phenotypes. Only the HDL cholesterol and triglyceride PRS were nominally significantly associated with ELL participants. In contrast and as expected, ELL individuals had higher polygenic risk scores for exceptional longevity (EL). In regards to the associations of the various cardiovascular PRS with EL, no findings survived correction for multiple testing. This is despite validating the utility of the lipid PRS by confirming positive associations with measured lipid levels in our sample. Interestingly, the different lipid PRS were based on GWAS that found a large number of genome-wide significant loci. ELL individuals had lower LDL and total cholesterol levels than controls in this study, but they did not differ on their respective PRS. This may suggest that environmental factors, perhaps lifestyle-related, influenced these lipid levels, which possibly promote longevity.

In contrast, the UK Biobank study observed that extreme parental longevity (defined as at least one parent who survived to the top 1% of age at death) had lower polygenic risk for several cardiovascular health measures. Namely coronary artery disease, systolic blood pressure, body mass index, high-density lipoproteins, low-density lipoproteins, and triglycerides. A similar result for HDL cholesterol and extreme parental longevity (EPL) by the UK Biobank to the current study was reported. Again, similar results were reported by the UK Biobank for LDL. However, the observed discrepancies between our analysis and the UK Biobank were most likely due to methodological differences, including the use of PRS that were based on different GWAS.

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Nicotinamide Riboside Reverses Age-Related Decline in Intestinal Stem Cell Populations

Nicotinamide Riboside Reverses Age-Related Decline in Intestinal Stem Cell Populations

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Nicotinamide riboside supplementation is one of the ways to increase levels of NAD+ in mitochondria, thus improving mitochondrial function. This probably does little for young people, particularly young and physically fit people, but in old age NAD+ levels decline along with mitochondrial function. Mitochondria are the power plants of the cell, and with aging they suffer a general malaise that is detrimental to tissue function, especially in energy-hungry tissues such as muscles and the brain. The causes are still poorly understood, though a faltering of the quality control mechanism of mitophagy due to loss of mitochondrial fission appears to be involved. Increased NAD+ appears to override this decline to some degree, albeit without addressing any of the underlying and still problematic root causes.

In early human trials, NAD+ upregulation has been shown to modestly improve vascular function in older individuals, most likely by reversing some of the dysfunction in smooth muscle cell behavior. In mice a broader range of benefits has been demonstrated, though it remains to be seen how many of those also appear in humans to a significant degree. The work here is more along the same lines, in which researchers show that nicotinamide riboside supplementation can restore intestinal stem cell function in older mice. This should improve tissue function, but again it is worth bearing in mind that this is only overriding a reaction to the underlying damage of aging – it doesn’t fix that damage, which still carries on to produce all of its other downstream issues.


Researchers have long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction. In 2016 it was found that, in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In a new study, researchers set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals. “That has real implications for health. Just having more stem cells is all well and good, but it might not equate to anything in the real world. Knowing that the guts are actually more stress-resistant if they’re NR-supplemented is pretty interesting.”

Link: http://news.mit.edu/2019/reverse-aging-intestinal-stem-cell-0328

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Mitochondrial Ion Channels in the Mitochondrial Dysfunction that Occurs with Aging

Mitochondrial Ion Channels in the Mitochondrial Dysfunction that Occurs with Aging

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Mitochondria are the power plants of the cell, present by the hundred in near every cell type in the body. They are important in many fundamental cellular processes, but their primary task is to package chemical energy stores in the form of adenosine triphosphate (ATP). Mitochondrial function declines with age in all tissues, and this is particularly problematic in energy-hungry tissues such as the brain and muscles. The cause of this decline may be failure of the quality control mechanisms of mitophagy, responsible for dismantling damaged mitochondria, or it may have deeper roots, such as loss of capacity for mitochondrial fission. Until some of those possible roots can be fixed reliably, it will be hard to assign relative importance to their contributions.

Given that mitochondrial function declines across the board, it will not be surprising to find that any given mechanism exhibits problems in older individuals. Mitochondria are wrapped in membranes, and those membranes use ion channels to pass various ions essential to their operation, such as calcium, back and forth. The open access paper here examines age-related mitochondrial dysfunction through the lens of ion channels and disruption of their activity. This seems likely a downstream issue, but as ever it is quite hard to determine cause and consequence in the mechanisms associated with aging without the ability to reliably intervene to fix just one thing in isolation.


Mitochondria are often referred to as the powerhouse of the cell, however, their physiological role goes well beyond that Mitochondria are highly dynamic organelles regulating their structure in line with metabolism, redox signaling, mitochondrial DNA maintenance, and apoptosis. Besides from generating adenosine triphosphate (ATP) for cellular energy, mitochondria are also deeply involved in providing intermediates for cellular signaling and proliferation. Mitochondria can alter their size and organization as a result of mitochondrial fission and fusion in response to various intracellular and extracellular signals. Fission and fusion events occur to meet metabolic demands and for the removal of damaged/dysfunction mitochondria. The role of mitochondrial fission and fusion in facilitating metabolism has been researched extensively. Fused mitochondrial networks typically engage more oxidative pathways of metabolism, whilst fragmentation as a result of stress impairs the oxidative pathway and increases cellular demand on glycolysis.

Ion channels are intimately involved in regulating mitochondrial function. The essential role of cationic hydrogen (H+) ion transfer in ATP production was noted as early as 1961. H+ ions are pumped from the mitochondrial matrix into the intermembrane space by the flow of electrons through the electron transport chain. These ions are then utilized to drive the ATPase machinery and phosphorylate ATP, thus creating energy for the cell. The movement of ions across the mitochondrial membrane is also essential in establishing membrane potential and maintaining proton (H+) flux. Ions transported across the inner membrane include potassium (K+), sodium (Na+) and calcium (Ca2+), alongside H+. The most well-studied ion channel within the mitochondrion is the voltage-dependent anion channel, VDAC, which is the primary route of metabolite and ion exchange across the outer mitochondrial membrane.

Mitochondrial channelopathies have been found in aging, affecting the K+, Ca2+, VDAC and permeability transition pore (Ca2+; PTP) channels. Mitochondrial Ca2+ cycling is impaired with aging in neurons, resulting from reduced Ca2+ channel activity and reduced recovery after synaptosomal stimulation. This reduced calcium recovery rate results in reduced mitochondrial membrane potential and delayed repolarization, causing mitochondrial dysfunction with aging. This effect has been found in the heart of 2 year old senescent rats. In terms of potassium channels, it has been shown that their density on the surface of mitochondria significantly declines with age and with metabolic syndromes in the heart sarcolemma. This has been shown to reduce tolerance to ischemia-reperfusion and increased injury in aged guinea pig and rat hearts, and also humans.

These effects have repercussions in increasing susceptibility to myocardial infarction and reducing neuronal activity in the elderly as mitochondrial K+ channels have been shown to play a neuroprotective role in neurological reperfusion injury in postnatal mouse pups. Amyloid-β plaques in Alzheimer’s disease have been shown to increase intracellular calcium levels. This increase in intracellular calcium, and uptake into the mitochondria through the VDAC and calcium uniporter, has been shown to increase mitochondrial stress responses and initiate apoptosis in rat cortical neurons in vitro and hippocampal slices ex vivo. Recent studies in Parkinson’s disease, have revealed that α-synuclein acts via the VDAC to promote mitochondrial toxicity of respiratory chain components in a yeast model of Parkinson’s.

Link: https://doi.org/10.3389/fphys.2019.00158

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Senolytic Treatment in Mice Improves Recovery Following Heart Attack

Senolytic Treatment in Mice Improves Recovery Following Heart Attack

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Senescent cells are a cause of aging. They accumulate with the passage of years and decades, a process that is in part just a matter of numbers and averages over time, in which a minuscule fraction of the vast number of newly senescent cells arising every day manage to evade destruction. Importantly, it is also due to the progressive failure of the immune system in its surveillance of errant cells. Senescent cells, like cancer cells, are attacked and destroyed by immune cells, and thus their numbers rise as immune cells become less competent. The harm done by senescent cells is mediated by the wide range of inflammatory, harmful factors that they secrete. The presence of even a small number of senescent cells disrupts tissue function, structure, and regenerative capacity.

As noted in today’s open access paper, the presence of senescence cells is important in the aging of the heart and the rest of the cardiovascular system. Cellular senescence contributes to ventricular hypertrophy, the process by which heart muscle becomes larger and weaker. Senescent cells are also implicated in the fibrosis found to disrupt structure and function of heart tissue; removing senescent cells via senolytic treatment reserves this fibrosis. Further, the chronic inflammation produced by senescent cells is generally harmful to the cardiovascular system, contributing to the progression of arterial stiffening via smooth muscle cell dysfunction, and atherosclerosis via macrophage dysfunction.

Senescent cells actively enforce their contribution to the state of aging via their secretions. Remove the cells, and that contribution vanishes, leaving behind downstream damage that can be repaired by cell populations to a sizable degree. Senolytic therapies to clear senescent cells have been demonstrated to extend life in mice, and turn back the progression of many aspects of aging and age-related diseases. Targeted destruction of senescent cells is a rejuvenation therapy, albeit a narrowly focused form of rejuvenation, targeting only one of many forms of damage that cause aging. The work here is one of many papers to demonstrate this point.

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction


Cellular senescence is classically defined as the irreversible cell cycle arrest of somatic cells. While senescence can act as a potent antitumour mechanism, recent studies have shown that senescent cells accumulate in several tissues with age where they contribute to age-dependent tissue dysfunction and several age-related diseases. Senescent cells are thought to contribute to aging via a pro-oxidant phenotype and the secretion of a senescence-associated secretory phenotype (SASP), which is pro-inflammatory, profibrotic, and can also promote senescence in surrounding cells.

Senescence has been shown to occur in the heart during aging and contributes to the pathophysiology of a number of cardiovascular diseases, as clearance of senescent cells in aged and atherosclerotic mice using both genetic and pharmacological approaches improves vascular and myocardial function and attenuates age-dependent remodelling. However, the impact of senescent cells in myocardial infarction (MI) has not been investigated thus far. In this study, we hypothesise that senescent cells contribute to the poor prognosis and survival of aged individuals following MI. Previously we found that in addition to clearing senescent cells, navitoclax treatment reduced fibrosis and cardiomyocyte (CM) hypertrophy in aged mice and considered that these beneficial effects may help to improve outcomes in aged mice following MI. We therefore performed a more detailed longitudinal study to examine this possibility and to explore potential mechanisms.

Histological analysis was performed on a cohort of noninfarcted mice, to assess the baseline effects of navitoclax treatment. In addition to decreasing CM hypertrophy, treatment reduced markers of CM senescence, indicating clearance of senescent cells from the hearts of treated aged mice. Furthermore, we found a significant reduction in expression of profibrotic TGFβ2, which we previously identified as a key component of CM SASP. Functionally, navitoclax treatment significantly reduced the age-dependent increase in left ventricular (LV) mass but did not impact on ejection fraction (EF). Aged mice also exhibited a decrease in the percentage change in diastole versus end systole LV wall thickness, indicating an increased LV rigidity compared with young animals, which was also partly rescued by navitoclax treatment. Clinically, increased ventricle stiffness is related to fibrosis and hypertrophy during aging, is symptomatic of diastolic dysfunction and is observed in heart failure with preserved ejection fraction patients.

We observed that aged mice had significantly higher mortality rates following MI (60% over 5 weeks) compared with young mice and that this outcome was rescued by prior navitoclax treatment. In contrast to young mice, old mice show a significant reduction in EF between 1 and 4 weeks post-MI. Importantly, navitoclax was able to rescue this functional decline which may help to explain the improved survival of this group. Furthermore, expression of senescence markers p16 and p21 at 4 weeks following MI was reduced in the hearts of navitoclax-treated mice, consistent with reduction of the senescence burden.

Collectively, this study shows that pharmacological clearance of senescent cells in aging mice alleviates age-dependent myocardial remodelling and attenuates expression of profibrotic mediators. Navitoclax improved the maintenance of cardiac function following MI, ultimately increasing survival. An important limitation of this study is that our experimental strategy was not able to distinguish which senescent cell types are responsible for this effect, and it is possible that clearance of senescent cells in noncardiac organs impact on survival following MI. We have focussed our attention on CMs in this study as our earlier findings showed that, in the heart, markers of senescence accumulate primarily in CMs during aging. However, further studies using animal models where senescent cells can be cleared in a cell-type specific manner are required to formally show the contribution of senescent CMs to cardiac recovery post-MI.

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Learned Helplessness as a Contribution to the Ubiquitous, Harmful Acceptance of Aging

Learned Helplessness as a Contribution to the Ubiquitous, Harmful Acceptance of Aging

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In a world in which nothing can be done about aging and inevitable death, acceptance is necessary. To remain sane and productive, to work towards a golden future that we will not live to see, requires a stoic viewpoint. One must accept the aspects of the world that are beyond control, and understand that we can control our own reactions to those aspects, so as to lead the best possible life under the circumstances. Aging has long been an aspect of the world beyond our control; one could endeavor to be more healthy rather than less healthy, but in the end there was still the inevitable decrepitude, suffering, and death.

Yet now biotechnology offers the near future possibility of the medical control of aging – and even today, the first rejuvenation therapies, those that selectively destroy senescent cells, are already available to anyone adventurous enough to try. In this environment, where funding, support, and the will to progress are all required to build out the full portfolio of means of human rejuvenation, acceptance of aging has become harmful and poisonous. It holds us back, and tens of millions of lives are the cost of every significant delay.


When you are repeatedly subjected to an unpleasant or painful situation over which you seem to have no control, there comes a point past which you simply give up on the very idea that you could possibly escape your predicament. Once you learn that you’re helpless in the face of circumstances beyond your control, you could end up simply accepting what is happening to you, even when the circumstances have changed enough to offer a way out.

We find this relevant because this learned helplessness could play a role in the pro-aging trance – or, at least, what happens in people’s minds because of the pro-aging trance is very much reminiscent of learned helplessness. If you’re new around here and have no idea what the pro-aging trance is, it’s basically one of the main drivers of irrational opposition to rejuvenation therapies; it’s the groundless conviction that aging is a blessing in disguise and that the fact that people age to death is actually good, despite the overwhelming, blatant evidence that this is not the case.

Even though you don’t spend your entire life with worsening eyesight, diabetes, cancer, or heart disease (to name but a few), you – like everyone else on the planet – were brought up with the notions that aging is inevitable and that one day it will kill you if nothing else does it first. You’re accustomed to the thought that, as you age, you will lose your health to at least some extent, and you have an idea of what you might be like in old age – weak, hunched over, easily fatigued, and with feeble senses and, if you’re unlucky, even more serious health problems. This idea is woven into every fiber of our society, arts, and institutions; even if you’re not exposed directly to the ailments of aging for most of your life, you are exposed to the unpleasant thought that your clock is ticking – a clock that measures not just the time you have left but also your remaining health – and that there’s no way that you could ever stop the clock.

In other words, you spend your entire life with the knowledge that your health is slowly declining, a decidedly unpleasant thing that, ultimately, you have no power to prevent. Therefore, you learn to accept it and make your peace with it, perhaps whimpering about it every now and again, but doing nothing else about it. Once the effects of aging manifest themselves in your old age, the feeling of helplessness gets even more real, as your health problems are no longer hypothetical and your doctor can essentially only help you manage your symptoms. This overall situation has much in common with the definition of learned helplessness.

Link: https://www.leafscience.org/learned-helplessness-and-the-acceptance-of-aging/

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UPD1 Gene Acts on the JAK/STAT Pathway to Regulate Life Span in Flies

UPD1 Gene Acts on the JAK/STAT Pathway to Regulate Life Span in Flies

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The data presented in this open access paper provides a good example of the complexity of the metabolic processes that influence life span. The researchers overexpress the UPD1 gene in various different tissues in flies. While the UPD1 protein acts via the JAK/STAT pathway in each case, the results on fly life span are wildly different. This sort of thing is exactly why it is very challenging, very slow, and very expensive to try to even modestly slow aging by tinkering with the operation of metabolism, to make an organism more resilient to the damage of aging. There are far better ways forward than this, notably those that involve periodic repair of the damage of aging.


The JAK/STAT signaling pathway is involved in many aging-related cellular functions. However, effects of overexpression of genes controlling JAK/STAT signal transduction on longevity of model organisms have not been studied. Here we evaluate the effect of overexpression of the unpaired 1 (upd1) gene, which encodes an activating ligand for JAK/STAT pathway, on the lifespan of Drosophila melanogaster.

Overexpression of upd1 in the intestine caused a pronounced shortening of the median lifespan by 54.1% in males and 18.9% in females, and the age of 90% mortality by 40.9% in males and 19.1% in females. In fat body and in nervous system of male flies, an induction of upd1 overexpression increased the age of 90% mortality and median lifespan, respectively. An increase in upd1 expression enhanced mRNA levels of the JAK/STAT target genes domeless and Socs36E.

Conditional overexpression of upd1 in different tissues of Drosophila induces pro-aging or pro-longevity effects in tissue-dependent manner. The effects of upd1 overexpression on lifespan are accompanied by the transcription activation of genes for the components of JAK/STAT pathway. As the JAK/STAT pathway is evolutionarily conserved it may be possible to discover compounds that fit the criteria of geroprotector. In our future work we plan to test the compounds from DrugAge and geroprotectors.org and other libraries potentially modulating upd, domeless and Socs36E on the lifespan of Drosophila and other organisms.

Link: https://doi.org/10.1186/s12918-019-0687-x

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Low Mitochondrial Permeability is Required for Autophagy to Extend Life Span

Low Mitochondrial Permeability is Required for Autophagy to Extend Life Span

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Mitochondria are the power plants of the cell, generating the chemical energy store molecule adenosine triphosphate (ATP) that powers cellular processes. Every cell possesses a herd of mitochondria, replicating like bacteria, and monitored by quality control mechanisms. Damaged, potentially harmful mitochondria are removed and dismantled for raw materials through a variant of autophagy called mitophagy. A mountain of evidence links mitochondrial function to aging, just as a mountain of evidence links the cellular recycling mechanisms of autophagy to aging. Both mitochondrial function and autophagic activity decline with age, producing downstream consequences that contribute to age-related diseases. There is the strong suspicion, with evidence to back it up, that it is the quality control of mitochondria, and thus maintenance of mitochondrial function without harmful side-effects resulting from damaged mitochondria, that is the common factor here.

Enhanced autophagy is a feature common to many of the methods by which aging can be slowed and life span extended in short-lived laboratory species. Most of these work via upregulation of cellular stress responses – to heat, lack of nutrients, oxidative damage, and so forth – and autophagy is an important stress response mechanism, making cells more resilient. Minor or short stresses lead to a longer upregulation of the response to stress, and thus the overall result is an improvement in health and longevity. This is called hormesis, and is a major part of the way in which intermittent fasting or calorie restriction work. Researchers have in the past demonstrated that calorie restriction actually fails to extend life in animals in which autophagy is disabled.

The topic for today is specifically the permeability of the mitochondrial membrane and its role in the relationship between mitochondrial function and autophagy. A fair amount of attention has been directed in recent years towards the mitochondrial permeability transition pore structures in the mitochondrial membrane, and their role in mitochondrial dysfunction. Clearly greater pore activity and thus greater permeability are a feature of aging, alongside mitochondrial dysfunction, but joining the dots on what is cause and what is consequence in our biochemistry is far from simple. It is known that mitophagy falters in later life, and it is known that this appears to be at least partly a consequence of reduced levels of mitochondrial fission – but consider how long it took to join just those two items. Why do mitochondrial fission rates fall? How does that relate to permeability and the membrane structures that support it? The complexity is overwhelming, which is perhaps why the path forward towards near term therapies is usually to cut the Gordian knot in some way, bypass the system that is poorly understood. Many of the SENS-style proposed rejuvenation therapies based on repair of underlying damage are of this form.

Mitochondrial permeability plays a key role in aging, recovery from ischemic injury


The ability of molecules to pass through the membrane of mitochondria – the cellular structures that convert nutrients into energy – may determine whether or not autophagy, a cellular process that removes damaged and dysfunctional molecules and cellular components, is beneficial or detrimental to the health of an organism. As the accumulation of damaged molecules and defective proteins is considered a hallmark of aging, autophagy has been associated with increased longevity. In fact, model organisms in which gene mutations or measures such as calorie restriction lead to lifespan extension depend on autophagy for their beneficial effects. However, autophagy can also play a role in cancer, diabetes, neurodegeneration and in the ischemia/reperfusion injury caused by restricted blood flow.

Previous studies have suggested that inhibition of the mTORC2 molecular pathway, which controls several critical metabolic functions, shortens lifespan. Organisms in which mutations in mTORC2 or in the gene encoding its downstream effector protein SGK-1 have reduced lifespan also show increased autophagy. Experiments revealed that inhibition of autophagy can restore a normal lifespan in mTORC2/SGK1 mutant C. elegans roundworms. The researchers also found that SGK-1 can regulate the opening of the mitochondrial permeability transition pore (mPTP), which allows very small molecules to pass through the mitochondrial membrane. Excessive opening of the mPTP, either by inhibition of the mTORC2/SGK-1 pathway or by direct genetic stimulation, transforms autophagy from a beneficial to a detrimental function, resulting in a shortened lifespan. Overall, the results indicate that the beneficial effects of autophagy depend on low levels of mitochondrial permeability.

Since autophagy is believed to contribute to ischemic injury, the investigators looked at its potential role in ischemia/reperfusion (I/R) injury – the exacerbation of tissue damage that occurs when blood flow is restored to tissue to which it had been restricted. They found that mice in which expression of the gene for SGK-1 was knocked out in the liver were more susceptible to I/R injury of the liver than were unmutated animals. While both current and previous research has indicated that elevated autophagy and mitochondrial permeability are harmful in the early phases of reperfusion injury, autophagy may help reduce the severity of tissue damage at later stages when damaged cellular components must be cleared from the cell.

Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension


Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan.

Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.

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