Escargot (esg) is a gene in the Snail family of genes in fruit flies. After a certain point, it doesn't really help all that much to peer too closely at the nomenclature of genes - it is best to just accept it and move on. Reduced levels of esg modestly extend life in flies, as researchers here demonstrate. As to why this is the case, here as in so many other cases, understanding is lacking. There are a few core mechanisms of plasticity in aging, linking the operation of cellular metabolism to natural variations in longevity between individuals. These largely relate to the activation of stress responses due to environmental circumstances, such as a lack of nutrients, but an enormous number of genes and proteins can influence those core mechanisms. The map of cellular biochemistry is far from complete in all of its details, and thus sometimes all that can be done is to look at relationships and speculate.

The nervous system is a key player in maintaining homeostasis and the structural and functional integrity of living beings and, hence, in controlling aging and longevity. Given the role of the nervous system in life span control, a reasonable question would be whether genes defining the cellular specificity of neurons are also involved, in some way, in the regulation of longevity.

We have already demonstrated that several genes that encode RNA polymerase II transcription factors and that are involved in neural development affect life span in Drosophila melanogaster. Among other genes, escargot (esg) was identified as a candidate gene affecting life span in a screen of more than 1,500 insertion mutations and the insertion located downstream of esg was further confirmed to be causally associated with life span control.

The gene esg belongs to the Snail family of genes that are involved in the development of the nervous system in arthropods and chordates. In Drosophila melanogaster, Esg and other Snail proteins act to control asymmetric neuroblast division during embryogenesis; however, Esg functions are not exclusively neuronal, and it also participates in the maintenance of intestinal and male germ cells, regulates tracheal morphogenesis and development of the genital disk, and determines wing cell fate.

Here, we present new data on the role of esg in life span control. Analysis of the esg-BG01042 mutation allowed us to show that esg is involved in the regulation of life span, to varying degrees, in unmated and mated males and females. The esg-BG01042 mutation also increased locomotion, specifically during old age, indicating that the mutation slowed down aging. The increase in longevity was caused by decreased esg transcription associated with structural changes in the DNA sequences downstream of the gene.

Targets of esg encoded enzymes involved in the biosynthesis of neurotransmitters, neuropeptides, cationic transporters, and other proteins. Among others, genes involved in the defense/immune response were both up- and down-regulated. Of the genes known to be involved in life span control, at least two genes associated with increased life span, heat shock protein 26 (hsp26) and NAD-dependent methylenetetrahydrofolate dehydrogenase (Nmdmc), increased transcription.

Link: https://doi.org/10.3389/fgene.2018.00151

Scaffold materials are widely used in regenerative research. They often take the form of gels, making it possible to inject and shape the scaffold in damaged internal tissue. These nanoscaled materials are mixed in with signal molecules that spur cell growth. The scaffold both supports cells structurally and encourages them to correctly rebuild natural tissue, complete with its extracellular matrix. The scaffold itself is degraded by cells and replaced by that tissue - at least in the ideal circumstance.

This has been demonstrated in a variety of tissues, particularly muscle, but here researchers have managed a much more challenging feat by convincing the brain to regenerate. It remains to be seen how well this restores lost function; that is much harder to evaluate in animals than the evident fact of structural repair. Nonetheless, this seems an important development. If the central nervous system can be induced to repair itself effectively, that will open a great many doors presently closed in the extension of human life.

In a first-of-its-kind finding, a new stroke-healing gel helped regrow neurons and blood vessels in mice with stroke-damaged brains. The results suggest that such an approach may someday be a new therapy for stroke in people. The brain has a limited capacity for recovery after stroke and other diseases. Unlike some other organs in the body, such as the liver or skin, the brain does not regenerate new connections, blood vessels, or new tissue structures. Tissue that dies in the brain from stroke is absorbed, leaving a cavity, devoid of blood vessels, neurons, or axons, the thin nerve fibers that project from neurons.

To see if healthy tissue surrounding the cavity could be coaxed into healing the stroke injury, researchers engineered a gel to inject into the stroke cavity that thickens to mimic the properties of brain tissue, creating a scaffolding for new growth. The gel is infused with molecules that stimulate blood vessel growth and suppress inflammation, since inflammation results in scars and impedes regrowth of functional tissue.

After 16 weeks, stroke cavities in treated mice contained regenerated brain tissue, including new neural networks - a result that had not been seen before. The mice with new neurons showed improved motor behavior, though the exact mechanism wasn't clear. "The new axons could actually be working. Or the new tissue could be improving the performance of the surrounding, unharmed brain tissue." The gel was eventually absorbed by the body, leaving behind only new tissue.

Link: https://www.eurekalert.org/pub_releases/2018-05/uoc--mrb051718.php

The glass half full view on exercise is that it modestly slows aging. The glass half empty view is that being sedentary accelerates age-related decline. Our species evolved in an environment that demanded considerably more physical activity than is the case in today's era of comfort, calories, and machineries of transportation. Lacking that activity, we suffer. There are any number of papers that provide evidence showing that a surprisingly large fraction of cardiovascular and muscle aging, loss of function and loss of strength, is preventable. Exercise can't stop aging, but it can certainly make a meaningful difference to quality of life along the way. If it was expensive, it might not be worth it. But it is free.

Today I'll point out a couple of open access papers that cover aspects of the effects of exercise on function and cellular biochemistry in later life. They are representative of current views on the interaction between physical activity, metabolism, and the progression of aging. As is the case for calorie restriction, one of the interesting puzzles in the matter of exercise and health is how it can manage to be beneficial and yet have a comparatively small effect on life span in our species. Short-lived species have a much more intuitive response: interventions that improve their health tend to lengthen life expectancy to a proportionate degree. Not so in humans.

In fact, I would say that one of our defining features as a species, in comparison to smaller mammals, is just how little our lifestyle affects our life span, even while producing a sizable range in health status. So in mice, just the application of calorie restriction can extend life by 40%, while in humans the overall difference in life expectancy between a terrible lifestyle and an optimal lifestyle is, at best, 15% or so. The scientific understanding of the details of aging and cellular metabolism is not yet at the point that would allow us to do more than speculate as to how this can be the case, even as the short-term benefits of exercise and calorie restriction in mice and humans look very similar.

The effect of lifelong exercise frequency on arterial stiffness

Central arterial stiffness increases with sedentary aging. While near-daily, vigorous lifelong (more than 25 years) endurance exercise training prevents arterial stiffening with aging, this rigorous routine of exercise training over a lifetime is impractical for most individuals. The aim was to examine whether a less frequent 'dose' of lifelong exercise training (4-5 sessions per week for more than 30 minutes) that is consistent with current physical activity recommendations elicits similar benefits on central arterial stiffening with aging.

A cross-sectional examination of 102 seniors (60 years and older), who had a consistent lifelong exercise history was performed. Subjects were stratified into 4 groups based on exercise frequency as an index of exercise 'dose': sedentary: fewer than 2 sessions per week; casual exercisers: 2-3 sessions per week; committed exercisers: 4-5 sessions per week; Masters athletes: 6-7 sessions per week plus regular competitions. Detailed measures of arterial stiffness and left ventricular afterload were collected.

Biological aortic age and central pulse wave velocity were younger in committed exercisers and athletes compared to sedentary seniors. TACi (total arterial compliance) was lower, while carotid β-stiffness index and Eai (effective arterial elastance) were higher in sedentary seniors compared to the other groups. There appeared to be a dose-response threshold for carotid β-stiffness index and TACi. Peripheral arterial stiffness was not significantly different among the groups. This suggest that 4-5 weekly exercise sessions over a lifetime is associated with reduced central arterial stiffness in the elderly. A less frequent dose of lifelong exercise (2-3 sessions/wk) is associated with decreased ventricular afterload and peripheral resistance, while peripheral arterial stiffness is unaffected by any dose of exercise.

Long-Term Exercise Protects against Cellular Stresses in Aged Mice

Regular exercise improves the physical capacity and reduces the risk of developing chronic and age-related diseases by improving the metabolic state, antioxidant protection, and redox regulation. Lifelong training was reported to slow down aging-associated skeletal muscle fiber atrophy and prevent the reduction in muscular strength. Notably, acute intensive exercise induces the production of reactive oxygen species (ROS) that can evoke macromolecular damage, oxidative stress, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response (UPR).

On the other hand, regular exercise training results in adaptations in antioxidant defense and improves redox signaling to protect cells against stress-related diseases, thus delaying the aging processes. In addition, the UPR, which is activated by exercise in skeletal muscles, may exert protective effects against ER stress and can promote metabolic adaptation to physical activity. Long-term exercise was reported to upregulate heat shock protein (HSP) production in skeletal muscle, which would be beneficial in coping with oxidative stress, ER stress, and ER stress-related apoptosis. Nevertheless, the ability to induce HSPs in aged skeletal muscle is compromised, which may impair the exercise-mediated adaptation processes.

There is only limited information available on the association of aging and exercise training concerning oxidative stress, ER (SR) stress, UPR, and/or ER stress-related apoptosis in skeletal muscle. Our hypothesis is based on the fact that there is an age-induced disruption of redox regulation, increased redox ER stress, and ER stress-related apoptosis, and that long-term exercise can exert protective effects against these processes. We investigated the key molecular markers associated with redox state, ER stress, and apoptosis in skeletal muscle of old animals in a life-long running model and compared them to young animals. Our data demonstrated that aging induced oxidative stress and activated ER stress-related apoptosis signaling in skeletal muscle, whereas long-term wheel-running improved redox regulation, ER stress adaptation and attenuated ER stress-related apoptosis signaling. These findings suggest that life-long exercise can protect against age-related cellular stress.

Arguably, age-related joint issues are where comparatively simple, first generation stem cell therapies have so far had their greatest and most reliable impact. To pick one example, mesenchymal stem cell therapies effectively reduce chronic inflammation for an extended period of time, achieving this result via the signals secreted by the transplanted stem cells in the comparatively short time they remain alive in the patient. Since arthritis is an inflammatory condition, and given that chronic inflammation interferes in the processes of healing, a reduction may spur some degree of increased tissue maintenance activity and repair. Reports suggest that this consequent regeneration is a lot less reliable than the reduction of inflammation, however.

Osteoarthritis (OA) is a prevalent debilitating joint disorder characterized by erosion of articular cartilage. The degradation of network of collagen and proteoglycan in OA cartilage leads to a loss in tensile strength and shear properties of cartilage. Interestingly, though OA manifests as loss of the articular cartilage, it also includes all tissues of the joint, particularly the subchondral bone. Besides aging, the increase in level of accumulation of advanced glycation end products (AGEs), oxidative stress, and senescence-related secretory phenotypes are a few reported factors associated with pathogenesis of OA.

The potential of stem cells to differentiate into osteoblasts, chondroblasts, and adipocytes, if stimulated properly, can regenerate cartilage both in vivo and in vitro. Recent progress in tissue engineering has highlighted the regenerative potential of stem cells for therapeutic purposes. The multilineage potential of stem cells, suitable scaffolds, and appropriate chondrogenic agent (chemical and mechanical stimuli) have been implicated to regenerate damaged cartilage. Mesenchymal stem cell (MSC) based therapy is also emerging as alternative to joint replacement with prostheses, due to its long-lasting effect.

MSCs derived from bone marrow (BMSCs) are capable enough to differentiate into tissues such as bone and cartilage and mobilize at an injured cartilage site in knee joints thereby assisting in cartilage regeneration in OA. In a study, the intra-articularly transplanted BMSC successfully regenerated injured cartilage in an animal model of OA and also improved osteoarthritic symptoms in humans without any major side effect even in the long-term. This study demonstrated the possibility of intra-articular injection of MSCs for the treatment of injured articular tissue including anterior cruciate ligament, meniscus, or cartilage. Therefore, if this treatment option is well-established, it may be minimally invasive procedure compared to conventional surgeries.

Link: https://doi.org/10.1155/2018/5421019

While regular moderate exercise appears to have only modest effects on overall longevity - five years or so at most, based on the epidemiological data - it does greatly improve long term health. The same might be said of avoiding weight gain, and thereby the consequences of excess visceral fat tissue. Studies suggest that some fraction of the decline of aging is self-inflicted, in the sense of being due to a lack of suitable exercise, gain of weight, smoking, and the like. While it isn't possible to avoid growing old, more of the unpleasant portions of aging can be evaded than is thought to be the case by the public at large. Being sedentary has real consequences when it comes to health and quality of life in later years.

New research has shown that older people with very low heart disease risks also have very little frailty, raising the possibility that frailty could be prevented. The largest study of its kind found that even small reductions in risk factors helped to reduce frailty, as well as dementia, chronic pain, and other disabling conditions of old age. Many perceive frailty to be an inevitable consequence of ageing - but the study found that severe frailty was 85% less likely in those with near ideal cardiovascular risk factors.

"This study indicates that frailty and other age-related diseases could be prevented and significantly reduced in older adults. Getting our heart risk factors under control could lead to much healthier old ages. Unfortunately, the current obesity epidemic is moving the older population in the wrong direction, however our study underlines how even small reductions in risk are worthwhile." The study analysed data from more than 421,000 people aged 60-69 in both GP medical records and in the UK Biobank research study. Participants were followed up over ten years.

The researchers analysed six factors that could impact on heart health. They looked at uncontrolled high blood pressure, cholesterol and glucose levels, plus being overweight, doing little physical activity and being a current smoker. "Individuals with untreated cardiovascular disease or other common chronic diseases appear to age faster and with more frailty. In the past, we viewed ageing and these common chronic diseases as being both inevitable and unrelated to each other. Now our growing body of scientific evidence on ageing shows what we have previously considered as inevitable might be prevented or delayed through earlier and better recognition and treatment of cardiac disease."

Link: https://www.eurekalert.org/pub_releases/2018-05/uoe-ih051718.php

Researchers have found that a physical mechanism in the brain, the flow of cerebrospinal fluid and the shear forces generated by that flow, influences the activity of neural stem cells via a distinctive set of biochemical signals. This will in turn influence the rate of neurogenesis, the creation of new neurons and their integration into existing neural networks. This process is important in learning, neurodegeneration, and the resilience of the brain when it comes to recovery from damage.

It is worth considering this recent discovery in the context of what is already known of reduced and impeded drainage of cerebrospinal fluid with age. The system of spaces through which cerebrospinal fluid circulates is not entirely closed off from the rest of the body, and normally drainage serves to remove metabolic wastes from the brain. It is thought that loss of drainage with age is an important contributing cause of the buildup of protein aggregates found in many neurodegenerative conditions, particularly the amyloid associated with Alzheimer's disease.

More generally, the production of cerebrospinal fluid declines with age, its fluid pressure falls, and the flow characteristics both change and diminish. It is well known that neurogenesis rates also fall with aging, at least in the well explored mouse brain, and setting aside the present controversy over the existence of adult human neurogenesis. That the fluid dynamics of cerebrospinal fluid ties into this aspect of aging is perhaps an important advance in understanding, given that we are likely to see an increased focus on this part of the brain's physiology from the Alzheimer's research community in the years ahead.

Flow of cerebrospinal fluid regulates neural stem cell division

Researchers have discovered that the flow of cerebrospinal fluid is a key signal for neural stem cell renewal. Neural stem cells in the brain can divide and mature into neurons and this process plays important roles in various regions of the brain - including olfactory sense and memory. These cells are located in what is known as the neurogenic stem cell niche one of which is located at the walls of the lateral ventricles, where they are in contact with circulating cerebrospinal fluid.

The cerebrospinal fluid fills the brain and its roles are still poorly understood. This work highlights the role of this fluid as a key signal - but this time not a chemical but a physical signal. The mechanism is controlled by the ENaC molecule. This abbreviation stands for epithelial sodium (Na) channel and describes a channel protein on the cell surface through which sodium ions stream into the cell's interior. "We were able to show in an experimental model that brain stem cells are no longer able to divide in the absence of ENaC. Conversely, a stronger ENaC function promotes cell proliferation."

Further tests showed that the function of ENaC is augmented by shear forces exerted on the cells by the cerebrospinal fluid. The physical stimulation causes the channel protein to open for longer time and allow sodium ions to flow into the cell, thus stimulating division. "The results came as a big surprise, since ENaC had previously only been known for its functions in the kidneys and lungs." Pharmacological ENaC blockers are already used clinically to relieve certain types of hypertension. Now it is known that they can also influence stem cells in the brain and thus brain function.

Epithelial Sodium Channel Regulates Adult Neural Stem Cell Proliferation in a Flow-Dependent Manner

One hallmark of adult neurogenesis is its adaptability to environmental influences. Here, we uncovered the epithelial sodium channel (ENaC) as a key regulator of adult neurogenesis as its deletion in neural stem cells (NSCs) and their progeny in the murine subependymal zone (SEZ) strongly impairs their proliferation and neurogenic output in the olfactory bulb.

Importantly, alteration of fluid flow promotes proliferation of SEZ cells in an ENaC-dependent manner, eliciting sodium and calcium signals that regulate proliferation via calcium-release-activated channels and phosphorylation of ERK. Flow-induced calcium signals are restricted to NSCs in contact with the ventricular fluid, thereby providing a highly specific mechanism to regulate NSC behavior at this special interface with the cerebrospinal fluid. Thus, ENaC plays a central role in regulating adult neurogenesis, and among multiple modes of ENaC function, flow-induced changes in sodium signals are critical for NSC biology.

PCSK9 inhibition therapies dramatically reduce cholesterol levels in the bloodstream, and seem set to take over from statins as the next generation approach to cholesterol management in the context of cardiovascular disease risk. Atherosclerosis results from the ability of a combination of damaged lipids - such as oxidized cholesterol - and overall level of lipids to overwhelm macrophage cells called in to clean up points of irritation in blood vessel walls. A feedback loop of inflammation and cell death sets in, as macrophages, filled with lipids and in the process of dying, call for further help, secreting cytokines that produce inflammation. The fatty deposits that weaken and narrow blood vessels in the later stages of atherosclerosis are composed of dead macrophages and the lipids they failed to clean up.

One way to try to slow down this runaway process of damage is to reduce the input of cholesterol. This is the basis of the success of statins in lowering cardiovascular risk, and the evidence suggests that further lowering of cholesterol levels will reduce that risk to a greater degree. This is still, however, only a stepping stone on the way to an effective and complete solution. PCSK9 inhibition doesn't halt or significantly reverse atherosclerosis, it still only slows it down somewhat. The research community must focus on different mechanisms and strategies, such as perhaps ways to make macrophages more resilient and more effective, allowing them to continue to operate in old people just as well as they do in young people. The SENS approach of removing oxidized lipids via delivery of bacterial enzymes is one example.

Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery.

Initial clues were provided by a French family with familial hypercholesterolemia (FH) in 2003. Gain-of-function mutations in PCSK9 were linked with hypercholesterolemia and ultimately uncovered a key new player in lipid metabolism. This seminal discovery led to a series of investigations that demonstrated that loss-of-function (LOF) mutations in PCSK9 associate with lifelong low cholesterol levels and marked reductions in the risk of atherosclerotic cardiovascular disease (ASCVD). The rare individuals with homozygous LOF mutations in PCSK9 (and no circulating protein) demonstrated extremely LDL cholesterol (LDL-C; ≈15 mg/dL), normal health and reproductive capacity, and no evidence of neurological or cognitive dysfunction.

This complementary set of observations has been leveraged into the most important therapy for the treatment of hypercholesterolemia and ASCVD since the introduction of statins. Indeed, the so-called PCSK9 inhibitors, fully human monoclonal antibodies that bind PCSK9, reduce LDL-C by ≈60% and risk of myocardial infarction and stroke by ≈20% after more than 2 years of treatment. Remarkably, these agents antagonizing PCSK9 action were approved by regulatory agencies spanning the globe only a decade after its discovery - although the scientific and medical communities have swiftly uncovered many facets of PCSK9 biology, there is still much to learn.

Link: https://doi.org/10.1161/CIRCRESAHA.118.311227

Senolytic compounds are those capable of selectively destroying senescent cells. They are useful because the buildup of senescent cells over time is one of the root causes of aging. A number of mechanisms have been discovered by which senescent cells can be provoked into self-destruction, such as bcl-2 inhibition or interference in FOXO4-p53 interactions. These examples are fairly well understood. Other mechanisms are known but less well understood; they require more work in order to proceed on the production of improved senolytic compounds.

In some cases, however, the primary mechanism of action of a compound found to be senolytic through experimental screening isn't yet known. The open access paper noted here is an example of how to move forward in this situation: the researchers report on their efforts to characterize the mechanism underlying the ability of piperlongumine to selectively destroy senescent cells. This line of work has been ongoing for a few years now; it takes time. Given sufficiently knowledge of the mechanism, however, it is usually possible to find or develop more effective candidate drugs in this family. Piperlongumine isn't perfect, and can be improved upon.

Cellular senescence occurs when irreversible cell cycle arrest is triggered by telomere shortening or exposure to stress. Senescent cells (SCs) accumulate if they cannot be removed rapidly by the immune system due to immune dysfunction and/or a sustained, overwhelming increase in SC production. This occurs during aging or under certain pathological conditions. Under these circumstances, SCs can be detrimental and play a causal role in aging, age-related diseases, and chemotherapy- and radiotherapy-induced side effects, in part through the expression of the senescence-associated secretory phenotype.

This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age-related diseases and disorders in both progeroid and naturally aged mice. Therefore, the pharmacological clearance of SCs with a small molecule, a senolytic agent that can selectively kill SCs, is potentially a novel anti-aging strategy and a new treatment for chemotherapy- and radiotherapy-induced side effects.

However, a major challenge facing the discovery and development of effective senolytic agents is to identify and validate more senolytic targets. Since the first senolytic was published, twelve molecular targets have been identified. These findings led to the discovery of a few senolytic agents, but the clinical application of these senolytic agents for age-related diseases and cytotoxic cancer therapy-induced side effects may be limited by agent toxicity and manufacturing challenges.

Piperlongumine (PL) is one of a few natural products identified to have the ability to selectively kill SCs. Compared to other known senolytic agents, PL has the advantage of low toxicity, an excellent PK/PD profile, and oral bioavailability. However, its molecular targets and mechanisms of action are unknown. To facilitate the development of PL and its analogues as senolytic drug candidates, it is critical to identify PL molecular targets, which can form a molecular basis for the rational design of new PL analogues.

Herein, we report the identification and validation of oxidation resistance 1 (OXR1) as a molecular target of PL in SCs. OXR1 is a cellular oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes and modulates the cell cycle and apoptosis. We found that OXR1 was upregulated in SCs induced by ionizing radiation or extensive replication. PL bound to OXR1 directly and induced its degradation through the ubiquitin-proteasome system in an SC-specific manner. Knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide (H2O2). These findings suggest that OXR1 is a potential senolytic target that can be exploited for the development of selective senolytic agents with improved potency and selectivity. In addition, these findings also provide new insight into the mechanism by which SCs are highly resistant to oxidative stress.

Link: https://doi.org/10.1111/acel.12780

The open access review paper I'll point out today covers numerous areas of cellular biochemistry relevant to aging wherein the nucleolus may have a role - though as is always the case, cause and effect in relationships with other aspects of aging are hard to pin down. As one might guess, this largely relates to stress responses, quality control, and damage repair within the cell. These line items are important in the way in which the operation of cellular metabolism determines natural variations in the pace of aging between species and between individuals within species. While the nucleolus is primarily responsible for building the ribosome structures where proteins are assembled, it has been found to play a part in a wide range of other cellular activities. Evolution tends to generate systems in which any given component has many and varied functions, and everything within a cell is connected to everything else.

This is an example of the broad, dominant class of aging research that is purely investigative. Most research into the detailed mechanisms of degenerative aging is very far removed from any thought of application, and it is lucky happenstance when such an opportunity does arise. Systems very closely tied to cellular housekeeping, or responses to stress, or replication seem unlikely to result in the foundations of truly effective therapies. We can look at calorie restriction or exercise, both of which alter all of the above items quite profoundly and throughout the body, to see the plausible benefits that might be attained through manipulation of these fundamental aspect of cellular behavior. Searching for means to adjust metabolism to modestly slow aging is not a winning strategy; the expected benefits are just not large enough. We must find ways to add decades of vigorous life, not just a few few healthy years.

Nucleolar Function in Lifespan Regulation

The nucleolus is an intranuclear organelle primarily involved in ribosomal RNA (rRNA) synthesis and ribosome assembly, but also functions in the assembly of other important ribonucleoprotein particles that affect all levels of information processing. Recent evidence has highlighted novel roles of the nucleolus in major physiological functions including stress response, development, and aging. Due to its crucial role in ribosome biogenesis, the nucleolus actively determines the metabolic state of a cell. In fact, the size of the nucleolus positively correlates with rRNA synthesis, which in turn is governed by cell growth and metabolism.

The nucleolus has been regarded as a housekeeping structure mainly known for its role in ribosomal RNA production and ribosome assembly. However, accumulating evidence has revealed its functions in numerous cellular processes that control organismal physiology, thereby taking the nucleolus much beyond its conventional role in ribosome biogenesis. Indeed, the nucleolus has been implicated in a number of other important functions including signal recognition particle (SRP) assembly, pre-transfer-RNA (tRNA) maturation, RNA editing, telomerase assembly, spliceosome maturation, and genome stability maintenance, thus more generally serving as a critical control site for ribonucleoprotein maturation as well as genome architecture.

There is also growing evidence ascribing a key role for the nucleolus in aging. Since the discovery of various genes and signaling pathways that regulate lifespan, there has been a dramatic expansion in the research on understanding the biology of aging. A number of hallmarks of aging, including genomic instability, telomere attrition, epigenetic modifications, and perturbations in proteostasis have been well established. Recent literature also highlights the crosstalk of different nucleolar functions with some of these hallmarks.

The target of rapamycin (TOR) pathway is a major pathway that integrates inputs on nutrients, growth factors, energy, and stress. When food is plentiful, it promotes cell growth and suppresses recycling processes like autophagy. When food is scarce it suppresses growth and promotes autophagy. Notably, TOR inhibition extends lifespan. Active TOR signaling has also been associated with elevated rRNA transcription in multiple studies. The TOR complex stimulates rRNA synthesis in the nucleolus. As nucleolar size correlates with rRNA synthesis, the TOR signaling pathway has correspondingly been shown to regulate nucleolar size.

Ribosome biogenesis is one of the most energy demanding processes in the cell. It is estimated that almost 80% of cellular energy reserves are required for ribosome biogenesis. Major perturbations in the cell have repercussions at the level of ribosome biogenesis and conversely, factors involved in ribosome biogenesis can regulate other processes. A number of studies have highlighted the role of ribosomal factors in regulating the lifespan of an organism. Downregulation of genes encoding multiple ribosomal proteins has been shown to extend lifespan in yeast and C. elegans. Though it remains to be tested if single ribosomal protein knockdown can have lifespan benefits in vertebrates, there is evidence suggesting that this might be the case.

The highly repeated structure of the ribsosomal DNA (rDNA) locus and its high rates of transcription make it particularly vulnerable to genome instability and damage. Multiple studies have reported a link between rDNA stability and cellular aging, as well as the association of proteins involved in genome integrity transiting the nucleolus. Aging in yeast is accompanied by nucleolar enlargement and fragmentation, suggesting a mechanism of cellular aging that may be related to nucleolar structure. Concordantly a recent study reported that the premature aging disorder Hutchinson-Gilford progeria syndrome leads to nucleolar expansion and increased ribosome biogenesis. Furthermore, there is evidence suggesting an association of replication stress on rDNA loci with the aging of hematopoietic stem cells, adding more evidence to the general function of the nucleolus in genome integrity and aging.

The nucleolus also impacts other vital cellular processes like the cell cycle and the response to cellular stress. One of the major tumor suppressor proteins central to regulating cell cycle is p53. The nucleolus acts as a platform connecting a cellular stress response with cell cycle through the central tumor suppressor p53. Interestingly multiple studies have implicated p53 in aging in different organisms. The nucleolus has also been associated with regulation of cell senescence. Alterations in nucleolar morphology have been reported in aging cells. In particular, presenescent cells exhibit multiple small-sized nucleoli compared to senescent cells which possess a single enlarged nucleolus.

The perception that the nucleolus is simply the place where ribogenesis takes place has clearly evolved. We now know that it is a highly dynamic organelle that coordinates signals from growth, energy, and stress to the balanced production and assembly of multiple ribonucleoprotein particles and the maintenance of genome integrity. This has ramifications for essentially all levels of molecular organization from genome architecture, RNA metabolism, protein synthesis and quality control to metabolism.

How much harm is done - and how quickly - by failing to maintain an exercise program? How long does it take to reverse those consequences? No-one has the final answer to those questions, firm numbers derived from the way in which the human body functions. We can look at the results of studies such as this one with some interest, however. We might compare this with studies of weight and mortality, in which the evidence suggests that lasting harm is done by carrying excess fat tissue over years, even if lost later.

By analyzing reported physical activity levels over time in more than 11,000 American adults, researchers conclude that increasing physical activity to recommended levels over as few as six years in middle age is associated with a significantly decreased risk of heart failure. The same analysis found that as little as six years without physical activity in middle age was linked to an increased risk of the disorder. "In everyday terms our findings suggest that consistently participating in the recommended 150 minutes of moderate to vigorous activity each week, such as brisk walking or biking, in middle age may be enough to reduce your heart failure risk by 31 percent. Additionally, going from no exercise to recommended activity levels over six years in middle age may reduce heart failure risk by 23 percent."

The researchers caution that their study was observational, meaning the results can't and don't show a direct cause-and-effect link between exercise and heart failure. But the trends observed in data gathered on middle-aged adults suggest that it may never be too late to reduce the risk of heart failure with moderate exercise. "Unlike other heart disease risk factors like high blood pressure or high cholesterol, we don't have specifically effective drugs to prevent heart failure, so we need to identify and verify effective strategies for prevention and emphasize these to the public." There are drugs used to treat heart failure, such as beta blockers and ACE inhibitors, but they are essentially "secondary" prevention drugs, working to reduce the heart's workload after dysfunction is already there.

The researchers used data already gathered from 11,351 participants in the long term Atherosclerosis Risk in Communities (ARIC) study, recruited from 1987 to 1989. The participants' average age was 60, and 57 percent were women. Participants were monitored annually for an average of 19 years for cardiovascular disease events such as heart attack, stroke, and heart failure using telephone interviews, hospital records and death certificates. Over the course of the study there were 1,693 hospitalizations and 57 deaths due to heart failure.

In addition to those measures, at the first and third ARIC study visits (six years apart), each participant filled out a questionnaire, which asked them to evaluate their physical activity levels, which were then categorized as poor, intermediate or "recommended," in alignment with guidelines issued by the American Heart Association. The "recommended" amount is at least 75 minutes per week of vigorous intensity or at least 150 minutes per week of moderate intensity exercise. One to 74 minutes per week of vigorous intensity or one to 149 minutes per week of moderate exercise per week counted as intermediate level activity. And physical activity qualified as "poor" if there was no exercise at all.

Heart failure risk decreased by about 12 percent in the 2,702 participants who increased their physical activity category from poor to intermediate or recommended, or from intermediate to recommended, compared with those with consistently poor or intermediate activity ratings. Conversely, heart failure risk increased by 18 percent in the 2,530 participants who reported decreased physical activity from visit one to visit three, compared with those with consistently recommended or intermediate activity levels.

Link: https://www.hopkinsmedicine.org/news/media/releases/six_years_of_exercise____or_lack_of_it____may_be_enough_to_change_heart_failure_risk

The author of this open access review of the study of growth hormone in aging is one of the eminent experts in this part of the field, noted for work on various loss of function mutant mice, lacking either functional growth hormone or functional growth hormone receptor genes. The current record for mouse longevity is held by a growth hormone knockout variant: these mice wouldn't survive in the wild, as they are small and vulnerable to cold, but they live 60-70% longer than their unmodified peers in the laboratory.

It is well documented that circulating levels of GH decline with age in various mammalian species, including humans, domestic dogs, and laboratory rodents. Yet in laboratory mice, disruption of growth hormone (GH) signaling leads to a remarkable extension of longevity. These findings were hard to interpret and were originally received with some skepticism because they implied that normal actions of a hormone have significant 'costs' in terms of longevity, and that a gross defect in the functioning of the endocrine system can have striking benefits for healthy survival. However, the evidence that absence of GH signaling extends longevity of mice is strong, reproducible, and now generally accepted.

Several aspects of the findings in GH-deficient and GH-resistant mice deserve particular emphasis. First, the significant extension of longevity in these animals is reproducible and not limited to a particular laboratory, diet, or genetic background. Second, lifespan is extended in both females and males. Third, extension of longevity is associated with a similarly striking extension of healthspan. Fourth, the magnitude of the increase in longevity exceeds the effects of most genetic, pharmacological, or dietary interventions that have anti-aging effects in mice.

A recent study examined longevity of mice lacking both GH and functional GH receptors. While these tiny 'double mutants' were remarkably long-lived compared to their normal siblings, they did not live significantly longer than mice lacking only GH or only GH receptors. In females, survival curves of GH-deficient Ames dwarf, GH-resistant GHRKO, and 'double mutant' (df/KO) animals were nearly identical.

The importance of GH signaling in the control of murine lifespan is further emphasized by the evidence that disruption of signaling events 'downstream' from GH and its receptor also extends longevity. Early findings of extended longevity of female mice heterozygous for the deletion of IGF-1 receptor were confirmed and extended in further studies. Major increase of longevity was seen in mice in which amount of bioavailable IGF-1 was reduced at the tissue level by germline or adult disruption of the gene coding for pregnancy associated plasma protein A, an enzyme degrading IGF-1 binding protein. Significant and reproducible extension of longevity was also produced by pharmacological suppression of the activity of mechanistic target of rapamycin, a kinase regulated by GH and IGF1.

Importantly, conclusions concerning pro-aging effects of normal or elevated GH based on studies in mutant, gene knockout, transgenic, or drug treated mice appear to apply to genetically normal mice and to other mammalian species. Multiple studies reported negative association of adult body size (a strongly GH- and IGF-1-dependent trait) with longevity in comparisons of different mouse strains, selected lines, and individual animals.

Link: https://doi.org/10.5534/wjmh.180018

No orthodoxy lacks accompanying heretics; it often seems that science is a business of proceeding abruptly and messily from one steady state consensus to another via the mechanism of heresy. It is of course worth bearing in mind that most heretics do turn out to be wrong, and are consequently forgotten by all but the most painstaking of scientific historians. In the paper I'll point out today, the orthodoxy of blood lipid levels as a cause of cardiovascular disease is challenged. The heresy is to suggest that it isn't the lipids at all, but all down to a matter of chronic inflammation.

This is a tough topic to arbitrate, because raised lipids, such as cholesterol, and raised inflammation go hand in hand. Dietary approaches to tackling cholesterol levels are minimally effective in the grand scheme of things, as dietary content is only a small factor in the lipid content of blood, but they also, inconveniently, tend to move the needle on inflammation as well. The calorie content of the diet, considered over the long-term, is linked to lipids and inflammation in equal measures via the amount of visceral fat tissue an individual carries. Therapies that are available and widely used to reduce blood cholesterol, such as statins, are shown to have anti-inflammatory effects. Therapies under development, such as delivery of the APOA1 protein that makes up the HDL particles responsible for dragging cholesterol out of vulnerable cells and transporting it to the liver, also have significant anti-inflammatory effects. You can probably see the challenge.

On the one hand, it doesn't seem completely unreasonable to mount the argument that lipid levels are a smokescreen, and we should be caring about chronic inflammation. We know that chronic inflammation is very damaging, and contributes to the progression of all of the common age-related diseases. When it comes to cardiovascular disease, and particularly atherosclerosis, it seems hard to write off a role for lipid levels in blood, however. Atherosclerosis is caused by oxidized lipids that overwhelm the cells sent to clean them up when they irritate blood vessel walls; the fatty deposits that narrow blood vessels are made up of lipids and dead cells. More lipids means more overwhelmed cells. Lower lipid levels means fewer oxidized lipids. But does that simple calculus hold up when looked at in detail? To answer that question, we need more data on highly effective therapies that are either anti-lipid or anti-inflammatory, but not both.

Inflammation, not Cholesterol, Is a Cause of Chronic Disease

According to the 'cholesterol hypothesis', high blood cholesterol is a major risk factor, while lowering cholesterol levels can reduce risk. Dyslipidaemias (i.e., hypercholesterolaemia or hyperlipidaemia) are abnormalities of lipid metabolism characterised by increased circulating levels of serum total cholesterol, LDL cholesterol, triglycerides, and decreased levels of serum HDL cholesterol. High levels of LDL cholesterol and non-HDL cholesterol have been associated with cardiovascular risk, while other cholesterol-related serum markers, such as the small dense LDL cholesterol, lipoprotein(a), and HDL particle measurements, have been proposed as additional significant biomarkers for cardiovascular disease (CVD) risk factors to add to the standard lipid profile.

HDL cholesterol has been considered as the atheroprotective 'good' cholesterol because of its strong inverse correlation with the progression of CVD; however, it is the functionality of HDL cholesterol, rather than its concentration that is more important for the preventative qualities of HDL cholesterol in CVD. In general, dyslipidaemias have been ranked as significant modifiable risk factors contributing to prevalence and severity of several chronic diseases including aging, hypertension, diabetes, and CVD. High serum levels of these lipids have been associated with an increased risk of developing atherosclerosis.

Furthermore, dyslipidaemias have been characterised by several studies not only as a risk factor but as a "well-established and prominent cause" of cardiovascular morbidity and mortality worldwide. Even though such an extrapolation is not adequate, it was, however, not surprising that this was made, because since the term arteriosclerosis was first introduced by pioneering pathologists of the 19th century, it has long been believed that atherosclerosis merely involved the passive accumulation of cholesterol into the arterial walls for the formation of foam cells. This process was considered the hallmark of atherosclerotic lesions and subsequent CVD.

Moreover, one-sided interpretations of several epidemiological studies, such as the Seven Countries Study (SCS), have highlighted outcomes that mostly concerned correlations between saturated fat intake, fasting blood cholesterol concentrations, and coronary heart disease mortality. Such epidemiological correlations between dyslipidaemias and atherosclerosis led to the characterisation of atherosclerosis as primarily a lipid disorder, and the "lipid hypothesis" was formed, which would dominate thinking for much of the 20th century.

On the other hand, since cholesterol is an essential biomolecule for the normal function of all our cells, an emerging question has recently surfaced: "how much do we need to lower the levels of cholesterol"? Furthermore, given the fact that cholesterol plays a crucial role in several of our cellular and tissue mechanisms, it is not surprising that there are several consequences due to the aggressive reduction of cholesterol levels in the body. Moreover, recent systematic reviews and meta-analyses have started to question the validity of the lipid hypothesis, as there is lack of an association or an inverse association between LDL cholesterol and both all-cause and CVD mortality in the elderly.

The principles of the Mediterranean diet and relevant data linked to the examples of people living in the five blue zones demonstrate that the key to longevity and the prevention of chronic disease development is not the reduction of dietary or serum cholesterol but the control of systemic inflammation. In this review, we present all the relevant data that supports the view that it is inflammation induced by several factors, such as platelet-activating factor (PAF), that leads to the onset of cardiovascular diseases (CVD) rather than serum cholesterol. The key to reducing the incidence of CVD is to control the activities of PAF and other inflammatory mediators via diet, exercise, and healthy lifestyle choices.

Today's good news is that the Alcor Life Extension Foundation, one of the two oldest US cryonics providers, has received a $5 million donation. Like a number of recent donations in our broader community, this originates from an individual who has done well in the growth of cryptocurrencies. I think that this philanthropy is a sign of things to come; these newly wealthy individuals are, on balance, younger and less set in their ways than those who come to wealth via the slower and more traditional means. They will be, accordingly, more adventurous, more disruptive, more supportive of causes that have a high utility but are not yet mainstream. This is all to the good, I feel.

This donation is an enormous sum for the non-profit cryonics community - it is a significant fraction of the existing Alcor assets, near all of which are locked up to support the long-term commitments of providing for its members. Cryonics is just as important to the cause of minimizing human death as the forms of medical biotechnology more usually featured here at Fight Aging! Sadly, it is also far worse off when it comes to the available resources, particular in the very necessary endeavor of research and development, to improve the state of the art, and produce a viable, self-sustaining industry based on reversible low-temperature storage of tissues. I would like to see this state of affairs change for the better, and this donation is a sizable first step on that road.

I am delighted to announce that Alcor has received a stunning $5,000,000 contribution to fund cryonics research. Alcor member Brad Armstrong (A-3000), came to visit Alcor in November 2016. After a tour and long and fascinating chat, before he left I suggested that he finally sit down and sign the membership paperwork. We would provide the witnesses and the Notary Public. 90 minutes later, Brad was done and handed us a check, making him a member. (See? It's not as difficult as you think.)

Fast forward to April 2018. Brad's assistant called to say that Brad wanted to make a major contribution to Alcor for the purposes of cryonics research. When I called Brad, I was immediately reminded that he is a down-to-earth, easygoing fellow who wants cryonics to work and is eager to fund what he knows matters. Brad is an enthusiast of cryptocurrencies and an admirer of Hal Finney - the first recipient and early developer of Bitcoin - and an Alcor member cryopreserved in August 2014. The $5 million research contribution is being held in the name of the "Hal Finney Cryonics Research Fund".

On behalf of Alcor and the cryonics effort in general, I want to say thank you. But how can I possibly express those thanks adequately? With a gift of this magnitude comes the responsibility of managing and spending it wisely for maximum impact. Until the Alcor board and Research Group determine how best to hold and use this funding, I have moved it from Alcor's bank account into a money market fund. Stay tuned as we determine how to use this remarkable influx of funding to boost Alcor's cryonics research.

Link: http://www.alcor.org/blog/unprecedented-5-million-contribution-to-cryonics-research/

Hydra are functionally immortal, given a suitably static environment. They exhibit continual proficient regeneration, and their mortality risk is low and constant over time. As a species they appear near unique in this. Why is aging and imperfect regeneration almost universal among species? One explanation is that environmental change gives aging species an advantage: non-aging species can certain emerge in eras of comparative environmental stability, but will be out-competed when the environment shifts. Other explanations involve the more complex structure in higher species, particularly in the central nervous system, where data must be stored as lasting molecular and cellular structures. Long-term persistence of fine cellular structure and proficient, continual regeneration don't go well together.

This study looks at the complexity and structure of the nuclear envelope inside cells as a possible dividing line between the few immortal species such as hydra and all of the others. The authors propose that increased complexity of the nuclear structure, and thus its greater vulnerability to certain kinds of molecular damage known to be associated with aging, limits the degree to which longevity and highly proficient regeneration can evolve - though I think that this is certainly something that could be argued either way, and at length.

The freshwater polyp Hydra represents a rare case of an animal with extreme longevity. It demonstrates unlimited clonal growth with no detectable signs of senescence, such as age-dependent increase in mortality or decrease in fertility, and thus is considered as non-senescent. Hydra body is made of cells of three lineages, originating from unipotent ectodermal and endodermal epithelial stem cells, and from multipotent interstitial stem cells. In contrast to most other animals, stem cells in Hydra indefinitely maintain their self-renewal capacity, thus sustaining non-senescence and everlasting asexual growth.

While unlimited self-renewal capacity of the stem cells is long recognized fundamental for Hydra's non-senescence, the underlying molecular mechanisms remain poorly understood. So far, the transcriptional factor FoxO was found as critical regulator of Hydra stem cell homeostasis and longevity, supporting the view that components of the insulin/insulin-like growth factor signaling pathways govern lifespan throughout the animal kingdom. Several other transcriptional factors are supposed to contribute to the non-aging of Hydra. However, the putative effector molecules downstream from these transcriptional factors that might contribute to the sustained stem-cell activity and non-senescence in Hydra remain unclear.

Studies in bilaterian animals propose proteins of the Lamin family to be the major effector molecules involved in the age-related cellular senescence and, hence, in the genetic control of ageing and lifespan. These highly conserved intermediate filament proteins form a complex network at the inner nuclear membrane, arrange the nuclear architecture and orchestrate multiple nuclear processes, such as DNA replication and repair, chromatin condensation, and transcription. Importantly, bilaterian cells are highly sensitive to the nuclear lamina disturbances. Decline in the expression level of Lamin B1 and increase of an aberrant Prelamin A isoform are associated with the age-dependent alterations in the nuclear lamina morphology and chromatin organization observed upon physiological ageing in mammals and invertebrates.

A homologue of vertebrate lamin B genes has been identified in Hydra, yet no efforts have been reported addressing the role of Lamin in cnidarian longevity. Here we present detailed analysis of the single Hydra lamin gene (hyLMN), its expression pattern, and distribution and function of its protein product (HyLMN). We demonstrate that proliferation of stem cells in Hydra is robust against the disturbance of Lamin expression and localization. While Lamin is indispensable for Hydra, the stem cells tolerate overexpression, downregulation, and mislocalization of Lamin, and disturbances in the nuclear envelope structure. This extraordinary robustness may underlie the indefinite self-renewal capacity of stem cells and the non-senescence of Hydra. A relatively low complexity of the nuclear envelope architecture might allow for the observed extreme lifespans of Hydra, while an increasing complexity of the nuclear architecture in bilaterians resulted in restricted lifespans.

Link: https://doi.org/10.18632/aging.101440

Since mitochondria seem to be the dominant theme this week, today I thought I'd point out a couple of recent open access papers that focus on the role of mitochondrial function (and dysfunction) in the neurodegeneration that accompanies aging. Every cell bears a swarm of mitochondria, the descendants of ancient symbiotic bacteria. Even though mitochondria long ago evolved into integrated cellular components, they still behave very much like bacteria in many ways. They multiply through division, and can fuse together and swap component parts, pieces of the molecular machinery necessary to their function. They also contain their own DNA, distinct from that of the cell nucleus.

The primary role of mitochondria is to undertake the energetic process of packaging chemical energy store molecules to power cellular operations. This is of particularly importance to energy-hungry tissues such as the brain, and why mitochondrial dysfunction with advancing age is thought to be especially relevant to neurodegenerative conditions. The evidence for this is more clear or less clear depending on which condition is discussed. In Parkinson's disease, for example, it is very evident that mitochondrial function is central to the characteristic loss of specialized neurons that drives the condition. For Alzheimer's disease, on the other hand, it is a real challenge to talk about the degree to which the numerous involved mechanisms are more or less important than one another. There is a lot of conflicting evidence.

The decline of mitochondrial function with age appears to have several distinct causes, not all of which are fully understood. Quality control mechanisms responsible for destroying errant and worn out mitochondria become less effective in later life. Some forms of mitochondrial DNA damage can produce mitochondria that are more resilient to quality control or more able to replicate than their peers, and they can take over cells to make them malfunction and cause harm. But aside from this, all mitochondria change profoundly in activity and structure in older individuals, and this may be a broad reaction to rising levels of molecular damage or other changes in signaling and cell behavior, above and beyond issues caused by failing quality control.

Brain Mitochondria, Aging, and Parkinson's Disease

High energy requirements tissues such as the brain are highly dependent on mitochondria. Mitochondria are intracellular organelles deriving and storing energy through the respiratory chain by oxidative phosphorylation. In a single neuron, hundreds to thousands of mitochondria are contained. Non-inherited mitochondrial DNA (mtDNA) mutations are called somatic mutations and appear over time. Mutated mtDNA replication is better when compared to wild-type mtDNA, which facilitates its clonal expansion. Once mutated mtDNA reaches at least 60%, the cell will have deficient respiration and will accumulate additional mtDNA mutations until cell death.

Somatic mtDNA mutations are important in aging and disease such as Parkinson's disease (PD). PD results mostly from the loss of dopaminergic neurons in the substantia nigra (SN). SN dopaminergic neurons are lost in an age and mitochondrial dysfunction related way. When compared to other neurons, SN dopaminergic neurons have more mtDNA deletions, where the load of mtDNA mutations parallels the deficiency of the respiratory chain.

Aging, at the cell level, is an increasingly incapacity to recycle organelles and macromolecules. Mitochondria DNA is very vulnerable. The aging process is tightly linked to mtDNA deletions and point mutations and to reactive oxygen species (ROS). Additionally, mtDNA deletions and point mutations accumulate over time. This leads to energetics impairment, increased ROS production, mtDNA lesions, and the decline of mitochondrial respiration.

Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism?

The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress.

To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded and aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (of expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurodegenerative diseases such as Alzheimer's, Parkinson's or even Huntington's diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.