Fight Aging! Newsletter, January 27th 2020

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit:

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  • Notes on the SENS Research Foundation Pitch Day, January 2020
  • ELOVL2 Upregulation Reverses Age-Related Decline in Vision Loss in Mice
  • We All Age in the Same Way, but with a Distribution of Outcomes
  • Inhibition of Autophagy in Mice Produces Signs of Accelerated Aging
  • Hypoxia-Inducible Factors in Vascular Aging
  • Sestrin Upregulation as an Exercise Mimetic
  • PAR1 Inhibition Activates Remyelination
  • Sticky Exosomes Can Worsen the Outcome of Stroke
  • Neural Stem Cell Derived Exosomes Improves Functional Recovery from Stroke in Pigs
  • MR1 as a Broad Signature of Cancer, Suitable for T Cell Targeting
  • Vascular Dysfunction as a Distinct Contribution to Cognitive Decline and Dementia
  • Immunosenescence and Loss of Resistance to Viral Infection
  • Aging Skin as a Significant Source of Systemic Chronic Inflammation
  • Immune Activity in Alzheimer's Disease as Both Friend and Foe
  • The Decline of Mitophagy in Age-Related Neurodegenerative Conditions

Notes on the SENS Research Foundation Pitch Day, January 2020

The J.P. Morgan Healthcare conference runs every year in San Francisco, a big draw for the biotech industry, and many organizations take the opportunity to host events at the same time. Among these, the SENS Research Foundation has for the past few years hosted a pitch day in which biotech companies in the longevity industry, largely startups, present to that portion of the Bay Area investor community interested in funding the treatment of aging as a medical condition. I was there to present on progress at Repair Biotechnologies, and took some notes on the other companies as they talked about their work.

Kimera Labs

Kimera Labs is a fairly established company working on exosome therapeutics and diagnostics, deriving the exosomes used in therapy from cultured stem cells. They have been around for 10 years or so, and started selling exosomes in 2014. They are primarily concerned with regenerative medicine applications, accelerating regeneration from severe injury via exosome delivery to produce faster healing without scar formation. Kimera Labs exosomes have been used to treat about 30,000 patients. The founder views the effects of stem cell exosomes as being a stimulation of growth signaling that is characteristic of embryonic development.

Viscient Biosciences

Viscient Biosciences works on 3D bioprinting of human tissues for drug discovery and validation, allowing for development programs that are, in their earlier stages, more cost-effective than those that must rely on animal studies. For example, they create liver organoids arrayed by the hundred on plates that are used in the processes of drug screening and testing. The company is founded by the former Organovo CEO. While they are not currently working on rejuvenation, the principals want to take their work into that realm of drug discovery.


OncoSenX is the spin-out from Oisin Biotechnologies that applies the Entos Pharmaceuticals fusogenic lipid nanoparticle platform to the task of selectively destroying cancer cells. These lipid nanoparticles are non-toxic, and one can thus employ very large doses without provoking immune reactions, widespread off-target cell death, or other issues. This is a big improvement over past generations of lipid nanoparticles. The DNA machinery carried by the lipid nanoparticles triggers the destruction of cells expressing the tumor suppressor gene p53. It doesn't matter if p53 is mutated and disabled, as is the case in many cancers, as the platform targets the earliest stages of the gene expression of p53, not the presence of p53 itself. The founder shared data from recent studies in immunocompetent mouse models of tumor development, showing that this approach results in a 100% rate of tumor clearance, a substantially better performance than checkpoint inhibitors can achieve in the same models.

Underdog Pharmaceuticals

Underdog Pharmaceuticals is one of the SENS Research Foundation spinout companies. The staff there work on removal of 7-ketocholesterol via the use of carefully designed cyclodextrin molecules that bind to it and carry it to the liver for excretion. 7-ketocholesterol is a form of persistent metabolic waste that has no useful role in the body; removing all of it would be a good thing. This toxic compound is important in the progression of atherosclerosis, but is also probably relevant to a range of other age-related conditions. is one of a growing number of groups working on forms of cellular reprogramming to reverse the epigenetic changes and loss of cell function that take place with aging. The approach uses mRNA delivery to achieve partial reprogramming, to shock cells over a few days into reversing their age-related epigenetic changes, without pushing them into abandoning their adult phenotype and function. The company presented gene expression profile data obtained from the use of their therapy in vitro, in which cells exhibited a shift to more youthful phenotypes without changing cell identity. In vivo they have assessed, for example, the impact of their treatment on muscle regeneration, showing lasting improvement in muscle regeneration in aged mice. They are also in the process of assessing delivery of their therapy to the retina to reduce age-related decline in visual function.


Gero is one of the present crop of AI-based drug discovery groups, using machine learning to speed up identification of therapeutics that might influence aging. They have produced results based on mouse and human data, and have identified a range of drug candidates, largely existing drugs that might be repurposed. They have tested these drugs in mice to assess slowing or reversal of aspects of aging; they view their approach as reducing damage, and think that clearance of senescent cells is probably an important factor in the results they are achieving in mice. The founders are now collaborating with Brian Kennedy in Singapore, and have moved there from their start in Russia.


Nemalife automates the process of screening interventions in C. elegans nematode worms, often used in early stage research in aging. Their product uses microfluidic chips to form a tiny habitat for C. elegans, combined with scanning technology and software, which results in a compact desktop device in which one can run this sort of study cost-effectively. Their differentiator is the small size of their system, which uses lesser amounts of reagents in comparison to other automation for C. elegans studies developed in recent years.

AgeX Therapeutics

Michael West took the floor to talk about about a relatively new subsidiary of AgeX Therapeutics called Reverse Bioengineering, which joins the other companies now working on applications of cell reprogramming. He noted that the cellular rejuvenation that occurs during reproduction, in the early development of the embryo, is the process that inspires these efforts. The AgeX staff are not just interested in changing the state of cells to make them younger, but also in making embryonic and embryonic-like cells older in phenotype. This artificial aging of cell phenotype has applications in producing cell lines and engineered tissues, to ensure that the cells are in the right state for adult function. The company is working on delivery of reprogramming therapeutics via exosomes as well as more traditional approaches. As to why regeneration is turned off in adults versus during embryonic development: the consensus is that this is a cancer risk reduction strategy, selected for by evolution. Cancers exhibit embryonic-like DNA methylation, they represent an inappropriate reversion to embryonic growth and regeneration, but these mechanisms are there to be exploited in a more controlled fashion.


Volumetric commercializes an advance in 3D bioprinting, a system that can incorporate blood vessel networks in the printed tissue that are sufficient to support larger tissue sizes. This has long been the roadblock that prevents serious work on whole organ engineering. This company is indeed aiming at the production of entire organs for transplantation, built from patient cells. They see the roadmap to that goal as starting with 3D printers, then the development of more advanced bioinks, then the creation of small engineered tissue models with complex architecture, and finally the creation of whole organs. Companies such as Volumetric will produce products at each stage that will support this progression; Volumetric is already selling the creation of engineered tissue models as a service.

712 North

712 North is focused on small molecule manipulation of mitochondrial pathways around OPA1, to promote either greater mitochondrial fission or fusion in order to treat specific conditions. More fusion can help some neurodegenerative conditions, while more fission might be the basis for cancer therapies. The company is initially looking at the inherited condition of autosomal dominant optic atrophy, in which there is OPA1 mutation. Looking ahead, OPA1 function changes in Alzheimer's disease in ways that produce results that look similar to those of the inherited condition in the optic nerve. Separately, there is evidence for OPA1 manipulation to reverse tau pathology in mouse models. This all further points to the importance of mitochondrial function in many conditions.


Qalytude is an adaptation of an existing business model for an easy online process to obtain prescription medications. The service uses physician and pharmacy networks to allow people interested in treating aging to obtain metformin, NAD+ patches, rapamycin, the senolytic therapy of dasatinib and quercetin, and so forth. They started with metformin, which I personally think people should not waste their time with, and are moving on to the other options. It is the provision of senolytics to the public at large that is the important part of their program, to my eyes at least. Given a subscriber community, the founders want to expand to conduct studies and gather health data.

Oisin Biotechnologies

Most of the readership here should be familiar with Oisin Biotechnologies, the first company to use the Entos Pharmaceuticals fusogenic lipid nanoparticle suicide gene therapy, in this case to target senescent cells for destruction. They see targeting cells based on their internal patterns of gene expression as the next stage in the evolution of cell targeting: more precise and adaptable than past technologies. The non-toxic lipid nanoparticles can be introduced throughout the body in high doses without side-effects, and the payload only triggers in cells that express p16, a characteristic sign of cellular senescence. The founders showed the full data for the mouse life span study that completed last year, and noted that treated mice didn't just live longer, but also exhibited increased bone density as measured via DEXA scans. They also showed good safety data from a small study carried out in companion animal dogs.

Leucadia Therapeutics

Leucadia Therapeutics works towards reversing the age-related decline in drainage of cerebrospinal fluid through the cribriform plate in the skull. In their model, this is a primary cause of Alzheimer's disease, as it allows metabolic waste to build up in the olfactory bulb where the condition starts. The founder discussed their animal data: they occluded the cribriform plate in ferrets, and as a consequence these animals suffered olfactory bulb degeneration and other aspects of Alzheimer's-like pathology. The company is presently focused on generating large amounts of human CT scan data, to produce an assay that determines who will progress from mild cognitive impairment to Alzheimer's, based an analysis of the state of the cribriform plate. Leucadia will then use the scanned population to determine who will benefit from a small medical device implanted in the cribriform plate to restore drainage of cerebrospinal fluid, and launch a clinical trial.

Repair Biotechnologies

Repair Biotechnologies is the company that I founded with Bill Cherman to work on regeneration of the thymus to address immunosenescence and reversal of atherosclerosis. We are continuing our path of preclinical development. I presented on recent progress in both of these programs, such as mouse data for improved immune function following upregulation of FOXN1 in the thymus, and visualizations of resistance to foam cell formation in a macrophage cell line that expresses enzymes capable of breaking down cholesterol.


Retrotope carries out human studies of treatment with deuterium loaded fatty acids, which are more stable and resistant to oxidative damage than the usual hydrogen-based fatty acids found in the body. The deuterium is very precisely placed - has to be in exactly the right place to avoid toxicity while increasing stability. When delivered as a therapy, replacing a modest percentage of the native fatty acids, these more stable fatty acids greatly reduce lipid peroxidation. The company has carried out clinical trials in an inherited infant neurodegenerative condition, caused by mutation in PLA2G6, and demonstrated reversal of this form of neurodegeneration. PLA2G6 is also implicated in Parkinson's disease, interestingly. The company has run clinical trials in Friedrich's Ataxia patients with good results, and obtained initial human data for progressive supranuclear palsy, showing reversal of the condition in three subjects.

Revel Pharmaceuticals

Revel Pharmaceuticals aims to commercialize glucosepane cross-link breakers based on the work funded by the SENS Research Foundation at the Spiegel Lab at Yale. The candidate enzymes were found via mining bacterial populations for species that can metabolize glucosepane, the primary basis for harmful persistent cross-links in humans. Collagen does not turn over all that much in adults, and these molecules get linked together or have their structure detrimentally altered via glucosepane cross-links. Cross-links accumulate steadily over time, from age 20 onwards, rising to pathological levels in later life. The founder noted that there have been trials of cross-link breaker small molecules in the past, but as of yet there are no successfully approved products.

Maia Biotechnology

Maia Biotechnology produces what they term telomerase-mediated therapeutics to target telomeres. This is perhaps the first group to attempt commercial development of a near universal cancer therapy based on suppressing tumor growth via interfering in telomerase and telomere function in cancer cells. They have developed a DNA sequence called THIO that, once introduced into cells, is incorporated into telomeres by telomerase activity. THIO sabotages cell function once present in telomeres, causing cell death. The founders presented in vitro data showing cell death in various cancers cell lines when exposed to THIO. THIO also combines well with PD-1 checkpoint inhibitors, when tested in mouse models of cancer, producing much better results than either on its own - actually completely clearing the tumors.

ELOVL2 Upregulation Reverses Age-Related Decline in Vision Loss in Mice

In today's open access research materials, the authors report that upregulation of the gene expression of an identified marker of aging, ELOVL2, can improve visual function in aging mice. Normally, expression of ELOVL2 declines with age, and consequent effects on visual function may involve the role of ELOVL2 in production of long-chain omega-3 and omega-6 polyunsaturated acids. These metabolites are in high demand in retinal cells, and lowered levels may well cause a sizable fraction of age-related dysfunction.

Any discussion of this change in ELOVL2 expression and visual function is interesting in the context of why degenerative aging takes place. It is clearly the case that considerable dysregulation of cellular metabolism takes place with age. The proximate cause of this degeneration of function is changes in the epigenetic regulation of gene expression, the pace of production of various proteins essential to cell function. In near all cases it is quite obscure as to why exactly these epigenetic changes take place - researchers are far more interested in identifying changes than in the much more arduous work of understanding the full context of any given change. The underlying damage of aging is well catalogued, such as in the SENS view of aging, but linking this damage through a long chain of downstream consequences to specific age-related functional consequences is a sizable project, still in its very earliest stages.

Researchers Identify Gene with Functional Role in Aging of Eye

A lengthy-named gene called Elongation of Very Long Chain Fatty Acids Protein 2 or ELOVL2 is an established biomarker of age. Researchers found that an age-related decrease in ELOVL2 gene expression was associated with increased DNA methylation of its promoter. Methylation is a simple biochemical process in which groups of carbon and hydrogen atoms are transferred from one substance to another. In the case of DNA, methylation of regulatory regions negatively impacts expression of the gene. When researchers reversed hypermethylation in vivo, they boosted ELOVL2 expression and rescued age-related decline in visual function in mice.

ELOVL2 is involved in production of long-chain omega-3 and omega-6 polyunsaturated fatty acids, which are used in several crucial biological functions, such as energy production, inflammation response, and maintenance of cell membrane integrity. The gene is found in humans as well as mice. In particular, ELOVL2 regulates levels of docosahexaenoic acid or DHA, a polyunsaturated omega-3 fatty acid abundantly found in the brain and retina. DHA is associated with a number of beneficial effects. Notably, its presence in photoreceptors in eyes promotes healthy retinal function, protects against damage from bright light or oxidative stress and has been linked to improving a variety of vision conditions, from age-related macular (AMD) degeneration to diabetic eye disease and dry eyes.

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina

Methylation of the regulatory region of the elongation of very-long-chain fatty acids-like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases.

We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2'-deoxycytidine (5-Aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration.

These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age-related eye diseases.

We All Age in the Same Way, but with a Distribution of Outcomes

Today's research materials are representative of numerous initiatives aiming to produce taxonomies of the biochemistry of aging, to catalog the observed variations. Yet, with the exception of a very small number of unlucky souls bearing rare harmful mutations, we all age for the same underlying reasons. The same processes of metabolism produce the same forms of cell and tissue damage, leading to the same downstream dysfunctions and the same ultimately fatal age-related conditions. Yes, there is some variation in outcome. For all that aging is a universally similar process of multiple interacting forms of damage, some portions of its consequences progress modestly more rapidly or modestly more slowly from individual to individual, a distribution of outcomes that largely results from lifestyle choices and random happenstance, rather than from genetic variation.

Thus many researchers are interested in this distribution, perhaps more so than in doing something about the challenge of aging, the death and suffering it causes. Given this view of the situation, I would say that somewhat more scientific effort goes into cataloging the differences between individuals than is merited. Examining long-lived people, with the goal of producing interventions that might make more people live incrementally longer in good health, is a terrible strategy, when compared with the alternative of directly addressing the common causes of aging, which might make everyone live considerably longer in good health. Nonetheless, despite the great potential of rejuvenation biotechnology based on repair of the damage that causes aging, there is a lot more funding and interest in the research community for far less promising lines of work.

'Ageotypes' provide window into how individuals age

Researchers profiled a group of 43 healthy men and women between the ages of 34 and 68, taking extensive measurements of their molecular biology at least five times over two years. The researchers determined that people generally age along certain biological pathways in the body: metabolic, immune, hepatic (liver) and nephrotic (kidney). People who are metabolic agers, for example, might be at a higher risk for diabetes or show signs of elevated hemoglobin A1c, a measure of blood-sugar levels, as they grow older. People with an immune ageotype, on the other hand, might generate higher levels of inflammatory markers or be more prone to immune-related diseases as they age. But the ageotypes are not mutually exclusive, and a metabolic ager could also be an immune ager, for example.

Just because an individual falls into one or more of the four ageotypes - metabolic, immune, hepatic and nephrotic - doesn't mean that they're not also aging along the other biological pathways. The ageotype signifies the pathways in which increases in aging biomarkers are most pronounced. Perhaps most exciting - and surprising - is that not everyone in the study showed an increase in ageotype markers over time. In some people, their markers decreased, at least for a short period, when they changed their behavior. They still aged, but the overall rate at which they did so declined, and in some cases aging markers decreased. In fact, the team saw this phenomenon occur in a handful of important clinical molecules, including hemoglobin A1c and creatine, a marker for kidney function, among a small subset of participants.

In that subset, there were individuals who made lifestyle changes to slow their aging rate. Among those who exhibited decreased levels of hemoglobin A1c, many had lost weight, and one made dietary changes. Some who saw a decrease in creatine, indicating improved kidney function, were taking statins. In other cases, exactly why rates of aging markers waned was unclear. For some people, there were no obvious behavioral changes, yet the team still saw a decreased rate of aging along their ageotype pathways. There was also a handful of people that maintained a slower-than-average aging rate throughout the entire study. How or why is still a mystery.

Personal aging markers and ageotypes revealed by deep longitudinal profiling

The molecular changes that occur with aging are not well understood. Here, we performed longitudinal and deep multiomics profiling of 106 healthy individuals from 29 to 75 years of age and examined how different types of 'omic' measurements, including transcripts, proteins, metabolites, cytokines, microbes, and clinical laboratory values, correlate with age. We identified both known and new markers that associated with age, as well as distinct molecular patterns of aging in insulin-resistant as compared to insulin-sensitive individuals. In a longitudinal setting, we identified personal aging markers whose levels changed over a short time frame of 2-3 years. Further, we defined different types of aging patterns in different individuals, termed 'ageotypes', on the basis of the types of molecular pathways that changed over time in a given individual. Ageotypes may provide a molecular assessment of personal aging, reflective of personal lifestyle and medical history, that may ultimately be useful in monitoring and intervening in the aging process.

Inhibition of Autophagy in Mice Produces Signs of Accelerated Aging

One must always be careful in the interpretation of studies of aging in which essential biological processes are disrupted. There are any number of ways to disrupt essential biological functions to produce all sorts of consequent damage. But damage that isn't relevant to the normal processes of aging can nonetheless produce results that look very much like age-related conditions. Thus the details matter greatly. Here researchers suppress autophagy in mice in order to gain greater insight into its role in aging, and suggest that there might be reasons for caution in the development of therapies to boost autophagy in old people - though again, the details matter greatly in any interpretation of this work.

Autophagy is the name given to a collection of cellular maintenance processes that work to recycle damaged protein machinery and structures. Autophagy declines with age, and this loss may be of greatest relevance when it comes to removal of worn and dysfunctional mitochondria. Mitochondrial function falters with age, which causes issues throughout the body, particularly in energy-hungry tissues such as the brain and muscle. This appears to be connected to a reduced effectiveness of mitochondrial autophagy, though the causes of this issue are still being investigated.

It is well known that many of the interventions known to slow aging in mice involve upregulation of autophagy, and some, like calorie restriction, will only slow aging and extend life if autophagy is functional. It is at present reasonable to conclude that autophagy is an important portion of the way in which the operation of metabolism steers the outcome of aging, but data resulting from the practice of calorie restriction in humans strongly suggests that the magnitude of the benefits that would result from therapeutic upregulation of autophagy just isn't as large as we'd all like it to be - though perhaps the upregulation just needs to be larger. We shall see in the years ahead, as biotech startups such as Selphagy Therapeutics make progress on clinical development of this class of therapy.

Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

Autophagy is an evolutionarily conserved bulk cellular degradation system that functions to breakdown and recycle a wide array of cytoplasmic components from lipids, proteins, and inclusion bodies, to whole organelles (e.g. mitochondria). Importantly a reduction in autophagic flux (the rate at which autophagosomes form and breakdown cellular contents) is associated with increasing age in mammals. Evidence from lower organisms suggests that autophagy inhibition can negate the positive-effects of regimens that extend lifespan, such as calorie restriction, rapamycin supplementation, and mutations in insulin signalling pathways.

In mice, the constitutive promotion of autophagy throughout lifetime has been shown to extend health- and life-span in mammalian models. These studies have provided hitherto missing evidence that autophagic flux can impact on mammalian longevity and supports the notion that the pharmacological promotion of autophagy may extend health-, and potentially life-span, in humans. However, whether a reduction in autophagy is sufficient to induce phenotypes associated with ageing, and whether these effects can be reversed by restoring autophagy has to date not been addressed. Considering that the therapeutic window for pharmacological intervention to counteract ageing, and age-related diseases, will be later in life (as opposed to from conception), after autophagic flux has declined, it is critical to understand how the temporal modulation (inhibition and restoration) of autophagy may impact on longevity and health.

To address these questions, we use two doxycycline (dox) inducible shRNA mouse models that target the essential autophagy gene Atg5 to demonstrate that autophagy inhibition in young adult mice is able to drive the development of ageing-like phenotypes and reduce longevity. Importantly we confirm that the restoration of autophagy is associated with a substantial restoration of health- and life-span, however this recovery is incomplete. Notably the degree of recovery is segmental, being dependent on both the tissue and metric analysed. A striking consequence of this incomplete restoration is that autophagy restored mice succumb to spontaneous tumour formation earlier and at an increased frequency than control mice, a phenotype not observed during autophagy inhibition alone. As such our studies indicate that despite the significant benefit, autophagy reactivation may also promote tumorigenesis in advanced ageing context.

Hypoxia-Inducible Factors in Vascular Aging

Stress response mechanisms have been shown to be important in the way in which metabolism determines longevity in any given species. Short-lived species exhibit great plasticity of life span in response to stresses such as heat, cold, nutrient deprivation, and hypoxia. A mild or transient stress can trigger lasting upregulation of cell and tissue maintenance activities, leading to improved function and a slowed aging process. Most such stress responses converge on the processes of autophagy responsible for recycling unwanted or damaged protein machinery and cell structures.

One of numerous lines of inquiry in this part of the field of aging research is focused on hypoxia-inducible factors (HIFs), proteins that manage the response to hypoxia, the stress resulting from insufficient oxygen to supply cellular operations. HIFs are involved in many age-related conditions, but their relationship with aging and disease is a complicated one. In some cases inappropriate overactivation of HIFs is harmful, such as in cancerous tissue. In the case of aging as a whole, HIFs may be involved in a range of processes that are both helpful and harmful. Thus a more careful exploration is required in order to pick out possible points of intervention.

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

Since the discovery of HIF-1α, several seminal works have identified the changes in HIF associated with age and the development of age-related disorders, including neurodegenerative diseases. Importantly, in 2009, researchers described HIF-1 as a longevity factor, demonstrating that HIF-1 stabilization is associated with a 30-50% increase in lifespan in nematodes. Several studies have shown that stabilization of HIF-1 increases longevity and healthspan through different pathways in Caenorhabditis elegans. These critical findings in worms yielded a new perspective on the study of HIF stabilization and lifespan among mammals. However, the stabilization of mammalian HIF-1α has been implicated in tumor growth and cancer development and may therefore be harmful. Consequently, a balance between the beneficial and detrimental effects of HIF is critical for homeostasis and depends on the involved components and their contribution to longevity.

Studies on skin, a tissue that is continuously exposed to intrinsic and extrinsic aging factors, have identified HIF-1α as a crucial determinant of skin homeostasis, especially in epidermal aging and wound healing. Results have reported that the loss of epidermal HIF-1α accelerates epidermal aging and affects re-epithelialization in humans and mice. Notably, significant elevations in both hypoxia-inducible transcription factors HIF-1α and HIF-1β gene expression have also been found in the gingival tissues of aged animals, even though these tissues were deemed clinically healthy. In a model of limb ischemia in mice, HIF-1 was found to mediate angiogenesis and, therefore, has been proposed to contribute to the pathological aging process.

HIF is not only a transcriptional factor that regulates tissue oxygenation (including angiogenesis and vascular remodeling) but also controls redox balance, inflammation, and glucose metabolism to eventually maintain cellular homeostasis. According to current knowledge, the age-dependent impairment of HIF-1α induction leads to diminished vascular responses to limb ischemia and less effective wound healing. Some evidence shows the functionally important expression of HIF-1α among ischemic limb mice. It has been demonstrated that the abundance of the HIF-1α protein is decreased in ischemic tissues from aged mice and has also been linked with the downregulation of genes encoding angiogenic growth factors. Another vital player of vascular aging, which is positively regulated by HIF-1, is vascular endothelial growth factor (VEGF), a central mediator of angiogenesis. During aging, there is a defect in HIF-1 activity, yielding VEGF expression reduction and leading to the impairment of angiogenesis in response to the ischemia model.

Recently, we found that HIF-1α is involved in p53, p16, cyclin D1, and lamin B1-mediated senescence in vascular endothelial cells (ECs). Moreover, senescent ECs failed to express HIF-1α, and the microvesicles released by these cells were unable to carry HIF-1α. In another study, HIF-1α was found to play a critical regulatory role in vascular inflammation of macrophages after an intimal injury, through limiting an excessive degree of vascular remodeling. The mechanism by which macrophage-derived HIF-1α mediated this effect is still unknown. Considering these findings, HIF-1α may represent a possible therapeutic target in vascular diseases, especially in vascular aging.

Sestrin Upregulation as an Exercise Mimetic

Researchers have been investigating the role of sestrin in longevity in lower animals such as flies and nematodes for some years now. Upregulation extends life, downregulation shortens life, and initial investigations suggested that the effect operates through the usual stress response mechanisms involved in life extension in short-lived species. Researchers here establish that sestrin in flies and sestrin-1 in mice are necessary for many of the benefits of exercise, and upregulation of sestrin mimics the effects of exercise on metabolism. There is also other published research in mice from recent years to support this role for sestrin-1 in mammals, in that expression of this gene is upregulated by exercise and also improves the operation of the cellular maintenance processes of autophagy.

One promising therapeutic intervention to impede age-related functional decline is endurance exercise. Endurance training induces remodeling in muscle tissue that alters the metabolic health of the entire organism. Evidence from humans and model organisms strongly suggests that endurance exercise has substantially protective effects on various indices of healthspan. These changes are often thought to be at least partially mediated by exercise-induced upregulation of AMP-activated protein kinase (AMPK) and the insulin-AKT pathway.

Sestrins are small stress-inducible proteins that are found throughout the animal kingdom. Mammals express three Sestrins (Sesn1-3), while Drosophila and C. elegans express one Sestrin orthologue. Once induced, Sestrins coordinate metabolic homeostasis by regulating multiple signaling pathways. Through its intrinsic oxidoreductase activity and by regulating autophagy, Sestrin can function as an antioxidant to reduce oxidative damage in cells. Importantly, while Sestrins downregulate TORC1/S6K signaling, they strongly activate TORC2/AKT signaling.

Here, using Sestrin-deficient fly and mouse models, we show that Sestrins play a critical role in mediating chronic exercise adaptations and exercise benefits. Genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism.

PAR1 Inhibition Activates Remyelination

Myelin is the sheathing of nerves, essential to their function. Excessive loss produces disabling and ultimately fatal conditions such as multiple sclerosis, but we all lose myelin integrity to some degree as a consequence of the damage and dysfunction of degenerative aging. This most likely contributes to cognitive decline and other age-related issues. A number of different approaches have been identified to boost the operation of the normal maintainance processes that remyelinate nerves, such as FGF21 upregulation, or increasing the size of remyelinating cell populations. Here, researchers discover another possible trigger that might force greater remyelination. While the work aims at treatment of conditions such as multiple sclerosis, successful remyelination therapies should in principle be useful for anyone in the later stages of aging.

Researchers have found that by genetically switching off a receptor activated by blood proteins, named Protease Activated Receptor 1 (PAR1), the body switches on regeneration of myelin, a fatty substance that coats and protects nerves. "Myelin regeneration holds tremendous potential to improve function. We showed when we block the PAR1 receptor, neurological healing is much better and happens more quickly. In many cases, the nervous system does have a good capacity for innate repair. This sets the stage for development of new clinically relevant myelin regeneration strategies."

Myelin acts like a wire insulator that protects electrical signals sent through the nervous system. Demyelination, or injury to the myelin, slows electrical signals between brain cells, resulting in loss of sensory and motor function. Sometimes the damage is permanent. Demyelination is found in disorders such as MS, Alzheimer's disease, Huntington's disease, schizophrenia, and spinal cord injury. Thrombin is a protein in blood that aids in healing. However, too much thrombin triggers the PAR1 receptor found on the surface of cells, and this blocks myelin production. Oligodendrocyte progenitor cells capable of myelin regeneration are often found at sites of myelin injury, including demyelinating injuries in multiple sclerosis.

The research focused on two mouse models. One was an acute model of myelin injury and the other studied chronic demyelination, each modeling unique features of myelin loss present in MS, Alzheimer's disease, and other neurological disorders. Researchers genetically blocked PAR1 to block the action of excess thrombin. The research not only discovered a new molecular switch that turns on myelin regeneration, but also discovered a new interaction between the PAR1 receptor and a very powerful growth system called brain derived neurotropic factor (BDNF).

Significantly, the researchers found that a current FDA-approved drug, vorapaxar, that inhibits the PAR1 receptor also showed ability to improve myelin production in cells tested in the laboratory. "It is important to say that we have not and are not advocating that patients take this inhibitor at this time. We have not used the drug in animals yet, and it is not ready to put in patients for the purpose of myelin repair. Using cell culture systems, we are showing that this has the potential to improve myelin regeneration."

Sticky Exosomes Can Worsen the Outcome of Stroke

Researchers here note a novel mechanism by which exosomes might cause issues following a stroke. Exosomes are a form of intracellular communication, membrane-bound packages of molecules that are released and taken up by cells in large numbers. Researchers are usually concerned with the way in which exosome cargo affects the behavior of cells once the exosomes are taken up, but here they note changes in exosome structure following a stroke that leads them to clump and block blood vessels. This is an interesting mechanism, and it will be equally interesting to see how the research community chooses to try to address it.

Researchers have found that after stroke, exosomes - nanosized biological suitcases packed with an assortment of cargo that cells swap, like proteins and fats - traveling in the blood get activated and sticky and start accumulating on the lining of blood vessels. Like a catastrophic freeway pileup, platelets, also tiny cells that enable our blood to clot after an injury, start adhering to the now-sticky exosomes, causing a buildup that can effectively form another clot, further obstruct blood flow to the brain and cause additional destruction.

One thing traveling exosomes typically aren't is sticky. Rather, much like our real suitcases, they have a smooth label that marks their intended destination. But when these external destination tags become inexplicably sticky following a stroke, not only do exosomes not reach their destination, they can worsen stroke outcome. In a bit of a perfect storm, the scientists have shown in both stroke models and human blood vessels that exosomes cruising through the blood then pick up RGD, the unique and normally sticky peptide sequence, arginine-glycine-aspartate, which is key to the pileup that can cause additional brain damage.

More typically, exosomes carry a negligible amount of RGD, a protein that's important in holding together the extracellular matrix that helps cells connect and form tissue. In the aftermath of a stroke, cells and the extracellular matrix both get damaged, and sticky RGD is effectively set free. Platelets normally aren't exposed to RGD, which should mostly be sequestered in the extracellular matrix, so they become angry, activated and also sticky in response.

Another piece of this sticky situation is that a receptor called αvβ3. Avβ3 also is found on the lining of blood vessels and naturally binds to sticky RGD as part of its role with the extracellular matrix. The new stroke study shows the RGD carrying exosomes also target these receptors. In fact, when scientists gave antibodies to αvβ3, the binding to the blood vessel lining was blocked. A bottom line of the new work is that RGD sequences are a key contributor to the secondary damage from stroke.

Neural Stem Cell Derived Exosomes Improves Functional Recovery from Stroke in Pigs

Delivery of exosomes derived from stem cell populations has been demonstrated to improve recovery from injury in numerous studies and human applications. The interesting aspect of this demonstration in stroke recovery in pigs is that exosomes from neural stem cells provoke greater functional recovery without improving some of the structural changes that are normally associated with greater mortality and loss of function.

Researchers have presented brain imaging data for a new stroke treatment that supported full recovery in swine, modeled with the same pattern of neurodegeneration as seen in humans with severe stroke. The researchers report the first observational evidence during a midline shift - when the brain is being pushed to one side - to suggest that a minimally invasive and non-operative exosome treatment can now influence the repair and damage that follow a severe stroke.

Exosomes are considered to be powerful mediators of long-distance cell-to-cell communication that can change the behavior of tumor and neighboring cells. The results of the study echo findings from other recent studies using exosome technology. Many patients who suffer stroke exhibit a shift of the brain past its center line-the valley between the left and right part of the brain. Lesions or tumors will induce pressure or inflammation in the brain, causing what typically appears as a straight line to shift. "Based on results of the exosome treatment in swine, it doesn't look like lesion volume or the effects of a midline shift matter nearly as much as one would think. This suggests that, even in some extremely severe cases caused by stroke, you're still going to recover just as well."

Trauma from an acute stroke can happen quickly and can cause irreversible damage almost immediately. Data from the team's research showed that non-treated brain cells near the site of the stroke injury quickly starved from lack of oxygen and died - triggering a lethal action of damage signals throughout the brain network and potentially compromising millions of healthy cells. However, in brain areas treated with exosomes that were taken directly from cold storage and administered intravenously, these cells were able to penetrate the brain and interrupt the process of cell death.

MR1 as a Broad Signature of Cancer, Suitable for T Cell Targeting

Meaningful progress towards the control of cancer, ending it as a major threat to life and health, will be led by programs that can produce very broadly applicable treatments. That means therapies that can be applied to many (or even all) cancers with minimal differences in configuration or need for further per-cancer development. There are hundreds of cancer subtypes, but only so many researchers, and only so much funding for research and development: development of highly specific therapies is just not an effective path forward.

Examples of the most promising lines of work with broad application include the OncoSenX suicide gene therapy targeting p53 expression, interference in telomere lengthening, and blocking immune inhibitors such as CD47 that cancer cells use to evade the immune system. Researchers here report on another possible approach, a very broad cell surface signature of cancer that might be used to build chimeric antigen receptor T cell immunotherapies that can be applied to a very wide range of cancers indeed.

T-cell therapies for cancer - where immune cells are removed, modified and returned to the patient's blood to seek and destroy cancer cells - are the latest paradigm in cancer treatments. The most widely-used therapy, known as CAR-T, is personalised to each patient but targets only a few types of cancers and has not been successful for solid tumours, which make up the vast majority of cancers. Researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognises and kills most human cancer types, while ignoring healthy cells. This TCR recognises a molecule present on the surface of a wide range of cancer cells as well as in many of the body's normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.

Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells - which express abnormal proteins - but ignore cells that contain only "normal" proteins. The scanning system recognises small parts of cellular proteins that are bound to cell-surface molecules called human leukocyte antigen (HLA), allowing killer T-cells to see what's occurring inside cells by scanning their surface. HLA varies widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people. The new study describes a unique TCR that can recognise many types of cancer via a single HLA-like molecule called MR1. Unlike HLA, MR1 does not vary in the human population - meaning it is a hugely attractive new target for immunotherapies.

T-cells equipped with the new TCR were shown, in the lab, to kill lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer cells, while ignoring healthy cells. To test the therapeutic potential of these cells in vivo, the researchers injected T-cells able to recognise MR1 into mice bearing human cancer and with a human immune system. This showed "encouraging" cancer-clearing results which the researchers said was comparable to CAR-T therapy in a similar animal model.

Vascular Dysfunction as a Distinct Contribution to Cognitive Decline and Dementia

The decline of the vascular system with age takes numerous forms, such as a loss of capillary density, stiffening of blood vessel walls leading to raised blood pressure and increased rupturing of small vessels, and leakage of the blood-brain barrier that wraps blood vessels in the central nervous system. This vascular degeneration is a distinct process from the accumulation of metabolic waste, such as amyloid-β, that characterizes neurodegenerative diseases. Age-related conditions tend to have numerous distinct causes that interact over time to make one another worse, and this is certainly true of the aging of the brain.

Three new studies add to growing evidence that damaged blood vessels wreak havoc on the brain, but not by exacerbating amyloid-β (Aβ) deposition. One found no correlation between intracerebral atherosclerosis and overall amyloid plaque burden in cognitively normal older adults. Another reported that midlife atherosclerosis in the carotid artery upped future risk of vascular dementia, but not Alzheimer's disease (AD). A third found that white-matter hyperintensities - a proxy for damage to small vessels in the brain - had no bearing on future changes in AD biomarkers.

"These studies can all be interpreted to support the hypothesis that vascular risk influences the risk for development of cognitive impairment and dementia principally via non-amyloidogenic pathways. They provide further evidence for, and are compatible with, the growing body of evidence that the timing of vascular risk also matters, with midlife being the most sensitive period. They all suggest that cerebrovascular disease and AD affect cognitive decline through distinct pathways."

On their own, faulty blood vessels in the brain can cause cognitive impairment and dementia. Blood-vessel disease is also thought to contribute to the clinical symptoms of AD, since people with Alzheimer's often have vascular pathology along with amyloid plaques and neurofibrillary tangles. Regardless of whether vascular dysfunction has an additive or synergistic relationship with AD pathology in influencing cognitive decline, the crucial point is that good blood vessel health benefits the brain. A person's vascular risk is highly modifiable by way of lifestyle choices or, if need be, medication.

Immunosenescence and Loss of Resistance to Viral Infection

The authors of this open access review paper discuss what is known of the age-related failure of the immune system, with a focus on the consequences for viral infection and vaccination effectiveness. The elderly suffer greatly because the immune system falters in its ability to protect against pathogens, a dysfunction that has numerous root causes. The atrophy of the thymus, reducing the supply of new T cells to a trickle; the disruption of hematopoietic stem cell function, reducing the pace of production of all immune cells; the fibrosis of lymph nodes, rendering it hard for immune cells to coordinate with one another; the accumulation of broken and harmful immune cell populations absent a supply of undamaged reinforcements. Potential strategies exist to address all of these issues; they must just be brought to realization by the research and development communities.

Immunosenescence is a major cause of increased incidence and severity of viral infections in the elderly, and contributes to impaired immunogenicity and efficacy of vaccines. Understanding the biological basis for age-associated alterations in viral immunity and vaccine immunogenicity is a challenge with substantial clinical importance. Subsequently, the use of systems biology approaches in combination with computational model systems will be crucial to understand the complexity of age-associated changes in the immune system by identifying molecular networks that orchestrate immunity to vaccinations in humans and potentially define correlates of protection.

Given the plastic nature of aging and rapidly growing field of systems biology, molecular profiling of the aging-related changes is increasingly being examined at a single cell level by high-throughput omics technologies, including genomics, metagenomics, transcriptomics, and metabolomics. Specially, aging of the immune cells is affected by changes in homeostasis via cytokine levels, and by modifications in the metabolic pathways. Caloric restrictions (CR) affected a marked improvement in the maintenance and/or production of naïve T cells and the consequent preservation of TCR repertoire diversity. Furthermore, CR also improved T cell function and reduced production of inflammatory cytokines by memory T cells, suggesting that CR can delay T cell senescence and potentially contribute to extended lifespan by reducing susceptibility to infectious diseases.

A key area for future exploration in the immunosenescence field is the role of the secondary lymphoid organs as a critical partner in the development and function of the aging human immune system. It will be important to analyze age-related changes in secondary lymphoid organs, lymph nodes and spleen, given the aging-associated decrease in the size of lymph nodes. Lymph nodes not only serve as the key initiating region of the immune response, but they also play an important role in maintaining naive lymphocytes.

Next, investigation of how extracellular vesicles (EVs) are linked to aging could be a promising area of interest. EVs are membrane-bound vesicles released by multiple cell types that include immune cells. Evidence from cellular models suggests that exosomes released by macrophages from older are more pro-inflammatory than those released by macrophage from younger. In particular, mRNA levels of IL-6 and IL-12, but not TNF-α, in macrophage-derived exosomes were significantly higher in serums of older subjects. Given that EVs play an important role in immune cell network and cellular senescence, the profiles of secretome and the function of senescent immune cells will soon be revealed as the EV research field progresses.

Aging Skin as a Significant Source of Systemic Chronic Inflammation

Researchers here propose that the skin is a significant source of the systemic chronic inflammation that is observed in older individuals. Setting aside the range of other mechanisms that contribute to inflammation to only consider the accumulation of senescent cells with age, and the fact that these errant cells are a potent source of inflammatory signaling, this proposition doesn't seem unreasonable. The skin is a sizable organ, after all, and even if it produces senescent cells at much the same pace as the rest of the body, it will still represent a large and quite distributed pool of such cells, positioned to delivery their inflammatory signals throughout the body.

Increasing evidence points to a provocative role of sustained, sub-clinical inflammation, often termed "inflammaging," in the development of these chronic disorders. In support of this notion, chronologically aged humans (≥50 years) display elevated circulating levels of pro-inflammatory cytokines, particularly IL-6, IL-1β, and TNFα. Moreover, subjects with chronic cutaneous inflammatory diseases, such as psoriasis and eczematous dermatitis, also display an increased prevalence of aging-associated disorders, including atherosclerotic cardiovascular disease, obesity, and type 2 diabetes. Though anti-inflammatory regimens, such as inhibitors of IL-1βα and TNFα, as well as methotrexate, have been deployed in the management of these aging-associated disorders, the outcomes of treatments with these agents have been inconclusive.

While many chronologically aged humans merely display marked evidence of inflammation, they nonetheless display elevated circulating levels of cytokines, suggesting that one or more, as yet identified organs, could account for the aging-associated increase in circulating cytokines. It seems reasonable to postulate that the responsible organs must be large enough to sustain such an increase in circulating cytokines, even without noticeable inflammation. Although the musculoskeletal system is the largest organ in humans, most chronologically aged humans display no evidence of musculoskeletal inflammation.

Other relatively large organs to be considered include the skin, intestines, lungs, and liver. The skin weighs about 20 lbs (with an additional, variable contribution from subcutaneous adipose tissues), while the weights of the intestines, lungs, and liver represent ≈7.5, 5.0 and 3.3 lbs, respectively. Because of their relatively lesser size, inflammation of the lungs, intestines, and liver likely would not only need to be apparent, but also sustained if any of these organs could account for the increase in circulating levels of cytokines. Yet again, the majority of otherwise normal aged humans display few clinical signs or symptoms of inflammation in these organs. Hence, it seems unlikely that they could contribute substantially to "inflammaging" unless multiple organs simultaneously exhibit mild inflammation. Notably, the aged skin commonly exhibits signs and symptoms of inflammation, such as pruritus and senile xerosis.

Because of its relatively large size, we hypothesized that the skin could be an important contributor to the elevated levels of circulating cytokines in chronologically aged humans, despite the fact that it typically displays little evidence of inflammation. Not only its size, but also its unique anatomic site, serving as the interface between the body and external environment, supports our hypothesis. In this site, it is continuously exposed to external physical and chemical stressors, which themselves can provoke inflammation, even as other less-exposed organs remain quiescent. In addition, chronologically aged humans display alterations in several key epidermal functions, each of which can provoke low-grade, chronic inflammation in the skin.

Immune Activity in Alzheimer's Disease as Both Friend and Foe

Chronic inflammation in brain tissue is thought to be important in the progression of neurodegenerative conditions such as Alzheimer's disease. Some factions within the research community theorize that chronic inflammation driven by dysfunctional microglia and other supporting cells in the brain is the important cause of Alzheimer's, not the early accumulation of amyloid-β. Even as it becomes inflammatory with advancing age, the immune system continues to perform necessary functions, however. So any approach to addressing the issue must be fairly selective. An example is the use of senolytic drugs capable of passing the blood-brain barrier in order to destroy senescent microglia and astrocytes, a strategy that, in mouse models, has been shown to reverse the tau pathology characteristic of the later stages of Alzheimer's disease.

While there is consensus that the immune system is intimately involved in Alzheimer's disease (AD), there is considerable debate over which aspects of inflammation are harmful and contribute to degeneration, and which are protective and may prevent cognitive decline. Furthermore, it has yet to be established which components of the immune system actively play a role in pathology and which are just a consequence of disease. Gliosis, or increased numbers of activated astrocytes and microglia are a hallmark feature of neuroinflammation. However, past descriptions of this phenomenon, namely just "reactive" or "increased gliosis" are vastly oversimplified. Recent evidence highlights altered glia-specific pathways in post-mortem AD tissue and in mouse models of AD, suggesting that glial responses are much more heterogeneous and complex than previously thought.

While neuroinflammation can promote efficient clearance of amyloid-β and neuronal debris it can also accelerate disease by causing neuronal and glial cell death. This inflammatory balance is highly orchestrated and understanding how to regulate these responses is key to developing effective therapeutics for AD. The initiation of an immunological reaction can be beneficial and critical, allowing for a burst of glial activity to protect and repair the site of damage, and to clear toxic species or dysfunctional synapses. For example, in response to adverse conditions, microglia will undergo morphological changes, accompanied by the release of a storm of molecular mediators that increases clearances of amyloid-β. Furthermore, various types of non-neuronal cells are recruited to the site to assist in repairing the damage and consolidating excessive inflammation. These reparative processes are beneficial, yet may also have harmful consequences such as sustained cytokine release which can become toxic to neuronal cells. Therefore, understanding the specific cellular roles and inflammatory reactions in AD is of vital importance.

The Decline of Mitophagy in Age-Related Neurodegenerative Conditions

Mitochondria are the power plants of the cell. A herd of these bacteria-like organelles in every cell manufacture the chemical energy store molecules that are used to power cellular processes. Mitochondrial function declines with age throughout the body. Evidence suggests that this is due to changes in mitochondrial dynamics that inhibit the quality control mechanisms of mitophagy that are responsible for recycling worn and damaged mitochondria. This loss of miochondrial function is well known to contribute to the progression of neurodegenerative conditions, as the brain is an energy-hungry organ, making this an important aspect of aging to target for reversal.

Mitochondrial health is vital for cellular and organismal homeostasis, and mitochondrial defects have long been linked to the pathogenesis of neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS, Huntington's, and others. However, it is still unclear whether cellular mechanisms required for the maintenance of mitochondrial integrity and function are deficient in these diseases, thus exacerbating mitochondrial pathology. The quality control of mitochondria involves multiple levels of strategies to protect against mitochondrial damage and maintain a healthy mitochondrial population within cells. In neurons, mitophagy serves as a major pathway of the quality control mechanisms for the removal of aged and defective mitochondria through lysosomal proteolysis. The molecular and cellular mechanisms that govern mitophagy have been extensively studied in the past decade. However, mitophagy deficit has only been recognized recently as a key player involved in aging and neurodegeneration.

Given the fact that mitochondrial deficit is clearly linked to neuronal dysfunction and the exacerbation of disease defects, protection of mitochondrial function could be a practical strategy to promote neuroprotection and modify disease pathology. Mitochondrially targeted antioxidants have been proposed. In particular, the antioxidant MitoQ, a redox active ubiquinone targeted to mitochondria, has been examined and demonstrated to have positive effects in multiple models of aging and neurodegenerative disorders. Importantly, mitophagy could be another promising target for drug discovery strategy. Therefore, further detailed studies to elucidate mitophagy mechanisms not only advance our understanding of the mitochondrial phenotypes and disease pathogenesis, but also suggest potential therapeutic strategies to combat neurodegenerative diseases.


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