Fight Aging! Newsletter, May 18th 2020

The rapidly aging U.S. population coupled with improved cancer survival rates has led to predictions of unprecedented growth in the number of cancer survivors over the next decade. Unfortunately, many modalities used to cure or control cancer damage healthy tissue, leading rate of functional decline) or accentuate the aging process (e.g., paralleled "normal" aging trajectory with weakened reserve). Data suggests that cancer survivors treated with adjuvant therapies are at risk for early onset of multimorbidity commonly seen in older patients. Estimates indicate that up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with cancer- and treatment-related comorbidities, including frailty, sarcopenia, cognitive impairment, and/or subsequent neoplasms. Adult cancer survivors report engaging in healthy behaviors at levels similar to adults with no history of cancer, and are more likely to adhere to physical activity recommendations. However, there are limited data on how physical activity and other strategies mitigate age-related conditions for cancer survivors.

Aging involves multifaceted, interdependent biological processes that can be altered by cancer and its treatments. The Geroscience Hypothesis postulates that many age-related conditions can be slowed or delayed by targeting hallmarks of aging (e.g., genomic instability, stem cell exhaustion, cellular senescence, inflammation, mitochondrial dysfunction, and epigenetic alterations). Given the complementarity of hallmarks that undergird aging, cancer, and cancer treatments, geroscience-guided interventions might delay or avert the age-related conditions observed in cancer survivors.

To consider emerging strategies that might prevent, mitigate or reverse cancer- and treatment-related aging consequences, the National Cancer Institute (NCI) convened the second of two think tanks under the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Emphasis was placed on therapies linked to age-related conditions or underlying aging processes (hallmarks of aging) that could be potential targets for interventions. Although several age-related processes provide potential targets for interventions, meeting discussions focused on cellular senescence. Cellular senescence is a cell fate that includes an irreversible proliferative arrest. Senescent cells accumulate in multiple tissues, and interestingly, transplanting small numbers of senescent cells into young animals induces frailty and age-related disease. Senescent cells also develop a pro-inflammatory senescence-associated secretory phenotype (SASP) that can disrupt tissue and immune function and create a permissive microenvironment for cancer growth.

Senescent cells are a promising target for aging interventions since these cells do not divide and can be eliminated by intermittent dosing using drugs with short half-lives. The SASP is also modifiable: it can be up- or down-regulated by hormones, pathogens, and drugs. Rapamycin, a mTOR inhibitor, is a promising agent that has been implicated in both aging and senescence. Rapamycin fed to older mice was shown to delay aging and extend lifespan. Senolytics have also achieved success in recent pre-clinical studies; notably, several senolytics are repurposed cancer drugs. The first trial in humans, a pilot, open-label study of dasatinib plus quercetin for idiopathic pulmonary fibrosis, a progressive, fatal, senescence-driven disease, was recently published. After nine doses over three weeks, participants showed improved physical function one-week later. If shown to be safe and effective in larger trials, the hope is that mTOR inhibitors and senolytics can be tested as preventatives of age-related conditions in cancer populations. Research is needed to determine the safety and efficacy of dosing intervals, and systemic, as opposed to local, administration.

Complex I (Cx I) (NADH-ubiquinone oxidoreductase) is an electron entry point in the mitochondrial respiratory electron transport chain (ETC). Cx I catalyses NADH oxidation reducing ubiquinone to ubiquinol, importantly contributing to the proton motive force used to synthesize ATP by the oxidative phosphorylation. Cx I also produce reactive oxygen species (ROS), initially superoxide radicals, which can damage all cellular components. Although at least 11 sites producing ROS have been identified, Cx I and complex III (Cx III) are conventionally recognized as the major sources of ROS at the ETC. Mitochondrial ROS production (mitROSp) has been considered one of the main effectors responsible for aging and longevity.

Low rates of mitROSp have been described in many long-lived mammalian and bird species. These studies generally demonstrated the existence of a negative correlation between mitROSp and longevity. Among the two main ROS generating ETC complexes, the low ROS production of various long-lived species has been localized at Cx I. Interestingly, different pro-longevity nutritional and pharmacological interventions like dietary restriction (DR) and methionine restriction, and rapamycin treatment have been also associated with decreased mitROSp at Cx I.

Mammalian Cx I is the largest component of the ETC built of 45 different subunits in mammals. Among the 14 core subunits, the 7 mitochondrial-encoded ND subunits are present in the hydrophobic membrane domain, and the other 7 nuclear-encoded (NDUF) subunits are present in the hydrophilic matrix domain. The 31 supernumerary NDUF accessory subunits are also nuclear coded. However, it is totally unknown if some particular Cx I subunits, especially some NDUF subunits of the Cx I hydrophilic domain, could be involved in the determination of the longevity-related low complex I ROS production of long-lived animal species.

The present study follows a comparative approach to analyse Cx I in heart tissue from 8 mammalian species with a longevity ranging from 3.5 to 46 years. Gene expression and protein content of selected Cx I subunits were analysed. Our results demonstrate: 1) the existence of species-specific differences in gene expression and protein content of Cx I in relation to longevity; 2) the achievement of a longevity phenotype is associated with low protein abundance of subunits NDUFV2 and NDUFS4 from the matrix hydrophilic domain of Cx I; and 3) long-lived mammals show also lower levels of VDAC (voltage-dependent anion channel) amount. These differences could be associated with the lower mitochondrial ROS production and slower aging rate of long-lived animals and, unexpectedly, with a low content of the mitochondrial permeability transition pore in these species.

GlycanAge is a British-Croatian start-up focused on analysing glycosylation patterns to deliver what it claims is the "most accurate" measure of biological age. Glycans are complex sugars that contribute significantly to the structure and function of the majority of proteins. Changes in glycans have been reported in many inflammatory diseases, where they reflect disease activity, or in some cases even precede the development of disease.

The company, leveraging patents from leading glycomics research lab Genos, has developed a direct-to-consumer glycan test kit that measures biological age and chronic low grade systemic inflammation. When the company first started in 2016, it worked using plasma samples, which was expensive and hard to scale commercially, but it has since developed a dry blood spot based test that delivers the same results.

"Telomeres are DNA timers that limit the lifespan of a single cell. On the individual cell level, telomeres are the best marker of aging. However, we are composed of trillions of cells and each of them has different age and expected lifespan. GlycanAge is different because it measures your immunoglobulin G glycosylation, which directly correlates with the level of inflammation in your body. It will give you information about the immune balance of your organism that changes with age, health and life circumstances."

GlycanAge is a science-based test that will accurately determine your biological age. This is a first commercial glycan-based test that will put a single number to your health. Glycans are complex sugar molecules (carbohydrates), and one of the four main building blocks of life. They are involved in almost every process in our body.

More than half of all our proteins are glycosylated, with their glycan parts often playing an essential functional role. Glycans are crucial for the functioning of our immune system. Glycans attached to the antibodies modulate their activity and determine if they will have a pro-inflammatory or anti-inflammatory function. Thus, it is not surprising that glycan profiles can serve as a measure of an individual's health. The GlycanAge test looks at the glycosylation pattern of the immunoglobulin G (IgG) molecule. IgG is the most prevalent antibody type in our blood and especially important in controlling inflammation and pathogens.

Immunoglobulin G (IgG), the most prevalent antibody type in our blood, is always glycosylated - meaning it has glycans attached to it. The type of the glycan group attached to the IgG determines if IgG will enhance or reduce inflammation. Since inflammation can exhaust our resources to keep the body in good health, low level of inflammation was shown to be a predictor of successful ageing. Therefore, IgG glycosylation is also a good measure of biological age.

The human gastrointestinal tract harbors a complex and dynamic population of microorganisms, referred to as gut microbiota. The gut microbiota is very important for the development and homeostasis of the body; it regulates intestinal motility and gastrointestinal barrier, host energy metabolism and mitochondrial function, as well as immune responses and the central nervous system. In adulthood, the microbiota reaches a relative equilibrium, and does not significantly change under stable environmental and health conditions. Generally, the phyla Bacteroidetes and Firmicutes dominate the intestine for adulthood. However, with an increasing age, the gut microbiota undergoes a profound remodeling. Researchers have shown that the gut microbiota of the elderly is substantially different from the younger adults, and correlates with frailty. However, given our current inability to delineate the most significant effector mechanisms involved in the host-microbiota interactions over a lifetime, it is difficult to tease apart causality from correlation.

Although some animal studies indicated that the gut microbiota affects learning and memory, these reports were based on special animal models, such as germ-free (GF) mice, or on various artificial interventions that change the gut microbiota, such as pathogenic bacterial infection, probiotics, and antibiotics. Since the aging process and aging biological characteristics were not considered in these studies, they were not able to uncover the association between gut microbiota and cognitive function under normal aging process. Given these findings, we hypothesized that alterations in the gut microbiota contribute to cognitive decline in aging. In this study, we transplanted the gut microbiota from aged rats to young rats by using the fecal microbiota transplantation (FMT) technique, to observe whether the reshaped gut microbiota can cause a shift in cognitive behavior, brain structure, and functions in the young recipient rats. To our knowledge, this is the first study that investigates the effect of gut microbiota on cognitive decline in normal aging process.

Results showed that FMT impaired cognitive behavior in young recipient rats; decreased the regional homogeneity in medial prefrontal cortex and hippocampus; changed synaptic structures and decreased dendritic spines; reduced expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor NR1 subunit, and synaptophysin; increased expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE). All these behavioral, brain structural and functional alterations induced by FMT reflected cognitive decline. In addition, FMT increased levels of pro-inflammatory cytokines and oxidative stress in young rats, indicating that inflammation and oxidative stress may underlie gut-related cognitive decline in aging. This study provides direct evidence for the contribution of gut microbiota to the cognitive decline during normal aging and suggests that restoring microbiota homeostasis in the elderly may improve cognitive function.

Recent studies argue for a pathogenic role of senescent cells, which contribute to a range of aging related diseases, such as osteoarthritis, cardiovascular disease, and cataract. Senescent cells are found in aging related cognitive decline but also in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Therefore, the possible application of senolytics in a wide range of clinical scenarios is becoming an attractive concept. Senolytics could be used as a preventative in the elderly, as a supplement to clear senescent cells to thus improve or maintain tissue and organ health. They are also being looked at as an adjuvant cancer therapy, with the aim of clearing treatment-induced senescent cells and thus reducing the probability of relapse.

Synthetic compounds with senolytic or senostatic properties can be effective, however, they are not specific, and systemic side effects can be severe and deleterious to healthy cells. Hence, a movement toward the research of natural based compounds (nutraceuticals) with potential anti-senescence properties has begun. Nutraceuticals are bioactive compounds derived from food, including plant material, with physiological benefits in the prevention or treatment of disease. For instance, polyphenols, found in high abundance in plants, are bio-active compounds with anti-oxidant and anti-inflammatory properties making them potential senostatics by negating the pro-oxidant and pro-inflammatory signaling of senescent cells. The aim remains to find potential anti-aging therapies that are effective but exhibit minimal side effects, and some natural plant-based compounds could fit this criterion.

In vitro, two olive phenols called hydroxytyrosol (HT) and oleuropein aglycone (OLE) have shown to counteract senescence via significant reductions in SA-β-Gal staining, p16 levels, and senescence-associated secretory phenotype (SASP) levels in human lung fibroblasts and neonatal human dermal fibroblasts. Catechin is a tannin found in green tea that exists in multiple forms, including Epigallocatechin gallate (EGCG). Research investigating the effects of EGCG against replicative senescence in cells has shown the potential senostatics effects of the nutraceutical. Fisetin is bioactive flavonol molecule. Naturally aged C57BL/6 mice treated orally at 22-24 months with 100 mg/kg fisetin for 5 days showed a reduction in senescent cells in white adipose tissue. Additionally, fisetin treatment at 85 weeks of age significantly prolonged life-span of these mice by an additional 3 months. Resveratrol treatment in endothelial progenitor cells (EPCs) also showed prevention of replicative senescence. However, when a large-scale in vivo study of resveratrol in genetically heterogenous (outbred) mice was conducted in parallel with rapamycin treatment, analysis of activity showed that there was no significant difference between control and resveratrol-treated mice.

For senolytics to be widely used in aged but otherwise healthy populations to prevent tissue dysfunction, unwanted side effects have to be kept to the minimum. The use of nutraceutical based senolytics could result in fewer complications, while retaining anti-senescent effects. Despite promising in vitro reports, the data on the in vivo efficacy of nutraceutical senolytics is still sparse and, in some cases, contradictory. Thus, more research is still needed to determine whether they could be an attractive alternative to the most used chemical senolytics, such as dasatinib + quercetin, which have shown promising results in preliminary short-term clinical trials.

Intensive blood pressure control may reduce the risk of atrial fibrillation (AFib), an irregular heartbeat that can lead to serious complications such as stroke, heart failure, and heart attacks. Researchers found that lowering a systolic blood pressure to less than 120 resulted in a 26% lower risk of AFib compared to systolic blood pressure of less than 140.

This analysis, using data from the National Institutes of Health Systolic Blood Pressure (SPRINT) trial, included 8,022 study participants who were randomized into one of two groups: 4,003 participants in an intensive blood pressure control group (target less than 120 mm Hg) and 4,019 participants in a standard lowering group (target less than 140 mm Hg).

Participants were followed for up to five years. During that time, only 88 AFib cases occurred in the intensive blood pressure lowering group while 118 cases occurred in the standard blood pressure lowering group. Researchers showed that the benefit of intensive blood pressure lowering on reducing the risk of AFib was similar in all groups of the participants regardless of sex, race, or levels of blood pressure.

Through all the daily updates on the sick and the dead, on testing and hospital capacity and changing public health guidance, there remains one constant: by far the greatest predictor of death from the COVID-19 pandemic is age. The so-called comorbidities predisposing patients to death from COVID-19 - chronic lung diseases, damaged kidneys and hearts, high blood pressure, diabetes - are themselves aspects of aging, erupting in their distinctive ways in particular tissues. Flattening this "demographic curve" of degenerative aging would reduce COVID-19 to a disease similar in impact to an average recent flu season (and make future flu seasons less deadly), while also putting an end to the staggering toll of age-related death and debility that ticks on in the background even now, day in and day out, pandemic or none.

The most obvious link between aging and COVID-19 is the aging of the immune system, or immunosenescence. Older people mount a much weaker and less complete immune response to both infection and vaccine, even as they suffer increasingly from overactive parts of the immune response, including autoimmunity and chronic inflammation. In today's pandemic, COVID-19 patients suffer from an exhaustion of natural killer (NK) and CD8+ ("killer") T-cells. Whereas T-cells and B-cells are specialists, focused on eliminating specifically-identified threats (such as cells infected with specific viruses), NK cells are sentinels patrolling the perimeter of a military camp, on the lookout for anything that looks like it doesn't belong. Long before the pandemic hit, we knew that NK cells lose much of their effectiveness with age, meaning that aging people already come into the fight against infections like SARS-CoV-2 with these critical early responders weakened.

We've known for a while that the age-related loss of lung function is a massive driver of risk of death from pneumonia. Aging people not only have fewer functional alveoli available, but progressively lose the ability to inhale and exhale deeply to compensate for alveoli taken offline by the infection. Continuing research suggests that eliminating senescent cells in the lung may preserve and restore youthful lung function, leaving the lungs better prepared to endure the attack of the SARS-CoV-2 virus and other causes of pneumonia. Senolytic drugs, which selectively kill senescent cells, have been shown to reverse lung fibrosis and other tissue fibrosis in aging mice. Studies in aging mice demonstrate that ablating senescent cells restores youthful lung compliance, suggesting an opportunity to do the same with other senescent-cell elimination strategies, such as restoring the ability of NK cells to eliminate them from tissues.

Like the pandemic, aging touches all of us. It creeps silently through our tissues, progressively crippling our minds and bodies, and eventually killing us if we don't die first of accident, violence, or other abrupt age-independent causes. In COVID-19, the damage caused by aging is the largest factor in determining who lives and who dies, even if the trigger was pulled by a virus spread by globalization. The need for rejuvenation biotechnologies as part of medicine has never been clearer, and so we strengthen our resolve. Restoring our cells and tissues to youthful vigor will allow us to step out of our ancient lockdown and into a bright future.

This meta-analysis showed a protective effect of physical activity to successful aging among the middle-aged and older adults. The protective effect of physical activity to successful aging was larger on the younger group than the older group. Being physically active in earlier life is beneficial to successful aging in later life. However, the effect of physical activity on successful aging decreased as time elapsed. Physically active middle-aged and older adults were more likely to age successfully than sedentary adults (odds ratio 1.64). The effect of physical activity was stronger in the younger group (odds ratio 1.71) than on the older group (odds ratio 1.54). The protective effect of physical activity reduced annually by approximately 3%.

Physical activity prevents the development of many chronic diseases, including metabolic syndrome, type 2 diabetes, coronary artery disease, hypertension, stroke, dyslipidemia, cognitive impairment, depression, osteoarthritis, osteoporosis, colon cancer, breast cancer, non-alcoholic fatty liver disease, and sarcopenia. Physical activity also increases longevity and survival. For middle-aged and older people, a dose-response relationship was found between physical activity and decrease in mortality. Compared with sedentary older people, physically active older adults were more likely to remain living independently. Physical activity in old age preserves the cognitive and physical functions. These previous findings supported the main finding of the present meta-analysis.

Physical activity is a protective factor of successful aging in the middle-aged and older adults. Although some included studies showed a weak association between physical activity and successful aging, most studies reported a consistent positive relationship. Further research is warranted to establish the dose-response relationship between physical activity and successful aging as well as to reduce the effects of time.

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data.

We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

Scientists have identified an unexpected player in the immune reaction gone awry that causes vision loss in patients with age-related macular degeneration (AMD). The findings suggest that an immune-stimulating protein called interleukin-4 (IL-4) and its receptor may be promising targets for new drugs to treat AMD, a common form of age-related vision loss. In patients with AMD, inflammation in the eye triggers excessive growth of new blood vessels in the center of the retina. This process damages the photoreceptors in the eye and leads to progressive vision loss.

The team measured levels of IL-4 in the eyes of 234 patients with AMD and 104 older individuals undergoing surgery for cataracts. They found that those with AMD had higher levels of IL-4 than those undergoing surgery. Next, they found that IL-4 was also elevated in mice with a condition that mimics AMD. To determine if IL-4 was helping or harming the animals, they administered them with IL-4 and found that it increased the excessive growth of blood vessels in the eye. An antibody that blocks IL-4 production reduced this blood-vessel growth. Mice with the AMD-like condition that were genetically engineered to lack IL-4 also had less blood-vessel growth.

"Our results show that IL-4 plays a crucial role in excessive blood-vessel growth by recruiting bone marrow cells that aid this growth to the lesion in the eye. These results were surprising and suggest that normally helpful immune responses can instead cause more harm,. As IL-4 plays a key disease-promoting role in AMD, it may serve as a target for new treatments to treat this condition." Normally, bone marrow cells help the body repair damaged tissues, while IL-4 helps suppress excessive blood vessel growth.

Nicotinamide adenine dinucleotide (NAD+) is a metabolite involved in numerous biochemical reactions. In particular, NAD+ is involved with electron transport where the reduced form (NADH) transfers electrons to other substrates and intermediates of metabolism. There is enthusiasm surrounding the role that tissue NAD+ concentrations play in the aging process, and researchers have determined skeletal muscle NAD+ concentrations are lower in older rodents and humans. These findings have led some to suggest that the age-associated loss in skeletal muscle NAD+ levels contributes to mitochondrial dysfunction. NAD+ biosynthesis can be catalyzed through the salvage/recycling pathway, and nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in this pathway. Beyond its involvement with redox reactions, NAD+ binds to and activates a class of enzymes that possess deacetylase activity called sirtuins (SIRTs).

Endurance training appears to be capable of increasing skeletal muscle markers related to NAD+ and SIRT signaling. For instance, endurance training in rodents and humans has been shown to modulate SIRT1 and SIRT3 protein levels and increase the activity of these enzymes in skeletal muscle. Additionally, skeletal muscle NAMPT protein levels have been reported to be higher in endurance-trained athletes versus untrained individuals. However, there is a paucity of research examining these biomarkers in response to resistance training. It remains plausible that resistance training can increase skeletal muscle markers related to NAD+ biosynthesis and SIRT signaling, and this may be an involved mechanism in facilitating training adaptations.

Given the paucity of data in this area, we sought to examine the effects of resistance training on skeletal muscle NAD+ concentrations as well as NAMPT protein levels, SIRT1/3 protein levels, and markers of SIRT activity in middle-aged, overweight, untrained individuals. In the middle-aged participants, the 10-week training intervention: i) promoted training adaptations (i.e., increased strength and localized hypertrophy), ii) robustly increased muscle NAD+ and NADH concentrations, iii) modestly (but significantly) increased NAMPT protein levels and global SIRT activity, and iv) robustly increased citrate synthase activity levels in muscle suggesting mitochondrial biogenesis occurred. This is the first evidence to suggest resistance training in middle-aged individuals restores muscle NAD+ and NADH concentrations to levels observed in recreationally-trained college-aged individuals.

Cardiac aging resulting in defects in cardiac mitochondrial function centers on the mitochondrial DNA (mtDNA) damage. The mechanisms of the alterations in the aging heart mainly involve mitochondrial dysfunction, altered autophagy, chronic inflammation, increased mitochondrial oxidative stress, and increased mtDNA instability.

Reactive oxygen species (ROS) play a pivotal role in healthy cellular and mitochondrial signaling and functionality. However, if unchecked, ROS can mediate oxidative damage to tissues and cells, leading to a vicious cycle of inflammation and more oxidative stress. Meanwhile, mitochondria, the major source of ROS, are thought to be particularly vulnerable to oxidative damage. Because of its richness in mitochondria and high oxygen demand, the heart is at high risk of oxidative damage. The most supportive evidence of the central role of mitochondrial ROS in the aged heart is that overexpression of catalase targeted to mitochondria attenuates cardiac aging.

A growing body of evidence suggests that there is increasing oxidative damage to mitochondrial DNA in cardiac aging. Because of the histone deficiency, limited DNA repair capabilities, and proximity of mtDNA to the site of mitochondrial ROS generation, mtDNA can suffer various types of damage, including mtDNA point mutations, mtDNA point deletions, and decreased mtDNA copy number (mtDNA-CN). The continuous replicative state of mtDNA and existence of the nucleoid structure render mitochondria vulnerable to oxidative damage and mutations.

DNA polymerase gamma (DNA Pol γ) plays a vital role in mtDNA replication. DNA Pol γ has two main functions: mtDNA synthesis and proofreading. Recent studies report that ROS reduces the proofreading ability of Pol γ, causing replication errors. Thus, oxidation aggravating mtDNA mutations causes replication errors, which indirectly cause mtDNA damage. This proves that mtDNA mutations are largely random, and Pol γ oxidation is likely to account for mtDNA mutations in aging. Therefore, mtDNA mutation may be highly associated with heart aging, and the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.

A decline in mitochondrial function is a hallmark of the aging process and is connected to other aging hallmarks such as telomere dysfunction, genome instability, and cellular senescence. However, it remains largely unclear how these processes are interconnected and finally provoke disruption of the cellular and tissue integrity. There is accumulating evidence that mitophagy impacts health- and lifespan in different model organisms. The effect of changes in mitophagy on health- and lifespan has been particularly demonstrated by using the model organisms C. elegans and D. melanogaster. Several genetic studies in D. melanogaster revealed that the overexpression of mitochondrial and mitophagy genes leads to increased health- and/or lifespan. For instance, the overexpression of the mitochondrial fission protein dynamin-related protein 1 (DRP1) increased the lifespan along with a prolonged healthspan in flies.

An increasing number of human diseases have been associated with impaired mitophagy, thus, interventions that modulate mitophagy may provide the possibility of counteracting disease development or progression. In recent years, multiple small molecules as well as lifestyle interventions have been shown to modulate autophagy, thereby causing health- and lifespan benefits in different organisms. Due to the dependency on core autophagy regulators, mitophagy is modulated by most of the classic autophagy inducers such as the mTOR inhibitor rapamycin, the AMP-activated protein kinase (AMPK) activator AICAR, as well as caloric restriction and exercise.

Mitophagy is emerging as a central process preserving organismal and, especially, neurological health. Since most trials targeting age-associated neurodegeneration in the last decades have been disappointing, new pharmaceutical avenues are direly needed. Here, mitophagy stimulators could play a key role. Indeed, several clinical trials are underway testing the efficacy of mitophagy modulating compounds and the outcome of these studies will undoubtedly prove critical for the future translatability of the field. Nonetheless, the regulatory mechanism of mitophagy and its contribution to age-associated diseases still remains elusive and potential issues with artificially augmenting mitophagy have not been considered. However, given the central role of mitophaging in multiple age-related pathologies it appears highly likely that these new promising approaches may present possible interventions in age-associated diseases. The future is bright!

Environmental exposures during early life exert a profound influence on developing organs, which can affect health across the life-course, and even transgenerationally. The adverse health impact of these exposures is thought to be mediated by reprogramming of normal physiologic responses, and forms the basis of the developmental origins of health and disease (DOHaD) paradigm. Fetal over- or under-nutrition has been linked to metabolic dysfunction in adulthood and increased risk for metabolic diseases including obesity, diabetes, and metabolic syndrome. Besides nutritional stressors, early-life exposures to environmental chemicals, including endocrine-disrupting chemicals (EDCs), can influence health and disease susceptibility across the life-course.

EDCs are defined as exogenous chemicals, or mixture of chemicals, that interfere with hormone action and many have been shown to impact metabolic function, and increase disease risk in metabolic organs such as the liver. Recently, the epigenetic machinery has emerged as a target for EDCs and other environmental exposures. When this machinery is perturbed early in life, the resulting epigenetic alterations can persist long after the initial environmental insult (often referred to as developmental reprogramming). Accordingly, research on the causes of the epidemic rise in metabolic diseases has expanded beyond genetics, over-nutrition, and energy expenditure to include the role of early-life EDC exposures. However, little is known about what determines vulnerability to early-life exposures, or specific targets and pathways linking developmental reprogramming by early-life exposures to later-life metabolic dysfunction.

Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid, and one-carbon metabolism.

Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin-like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear.

We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock-down of Alk, or expression of dominant-negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin-like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism-wide insulin-like signalling. Finally, we show that TAE-684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.