Fight Aging! Newsletter, April 20th 2020

Cellular senescence is a state of irreversible cell cycle arrest in response to an array of cellular stresses. An important role for senescence has been shown for a number of pathophysiological conditions that include cardiovascular disease, pulmonary fibrosis, and diseases of the skin. As a central mechanism, senescent cells can impact the surrounding tissue microenvironment via the secretion of a pool of bioactive molecules, termed the senescence-associated secretory phenotype (SASP). However, whether senescence contributes to the progression of age-related macular degeneration (AMD) has not been studied in detail so far.

Acute senescence is mostly beneficial and presumably does not contribute to aging; it relies on the coordinated action of senescent cell production and subsequent elimination - the processes involved in wound healing, tissue remodeling, and embryogenesis. Paradoxically, while chronic senescence can initially have beneficial effects, its long-term existence could potentially aggravate age-related diseases. "Chronic" senescence develops gradually because of progressive damage over time as seen in aging and age-related diseases. During chronic senescence, the switch from temporal to persistent cell cycle arrest appears to be random, induced by the multiple inducing factors acting simultaneously on a cell. These results in arrest of proliferation and ultimately cells become dysfunctional and most importantly negatively affect local environment.

Aging is considered one of the most obvious predisposing factors for the development of AMD because prevalence of this disease rises in those over 60. With aging, the human retina undergoes various structural and physiologic changes. Several independent studies suggest senescence contributes to the development of many ocular diseases. Aging has been associated with fewer retinal neurons along with numerous age-related quantitative alterations such as decreased areas of dendritic and axonal arbors and decreased density of cells and synapses. One study found that retinal pigment epithelium (RPE) cells were lost in large numbers in the periphery of the human retina while a second study reported overall RPE to photoreceptor ratio dropped with age throughout the retina. Furthermore, protein levels of canonical senescence markers such as p16, p21, and p53 were shown to increase in the RPE isolated from aged human donors.

Retinal microaneurysms overexpress canonical senescence markers, suggesting that cellular senescence is associated with the pathogenesis. Apoptosis also cooccurs with cellular senescence in old-age retinal microaneurysms. The age-related decrease in the anterior segment outflow is largely responsible for the elevated intraocular pressure, one of the factors attributing to the development of glaucoma. Markers of cellular senescence are found in the trabecular meshwork of patients with primary open-angle glaucoma and aging of these cells leads to their decreased function and a consequent decreased outflow facility.

Beyond loss of retinal cells, aging is also associated with the accumulation of both intracellular and extracellular deposits. The finding that amyloid-β (Aβ) is also elevated in aging retina and is a component of drusen suggests that Aβ may be a key factor in AMD pathology. Aβ has been recently shown to induce RPE cells to enter senescence. A recent study shows the role of RPE senescence in the retinal degeneration induced by Aβ peptide as characterized by upregulation of senescence markers. Hence, cellular senescence of RPE or neuronal cells induce different age-related retinal diseases and targeting them could be a viable therapeutic strategy.

Clearance of senescent cells is an important role of the adaptive immune system in relation to healthy aging. This regulatory role can be compromised by aging itself, HIV infection, or many other immune stressors that weaken immune function and/or promote immunosenescence. The deficits in adaptive immunity observed in HIV/CMV co-infection, accompanied by an increased prevalence of age-associated pathologies termed accelerated aging, together comprise a unique setting within which to study senescent cell accumulation and its physiological impact.

Immunological stress, as imposed by chronic infection, chronic inflammation, or requirements for homeostatic proliferation, can promote progression of lymphocytes to cellular senescence and impose immune deficits that impair clearance of senescent cells from tissues, thus, compounding the accumulation of senescent cells and the negative implications of their senescence-associated secretory phenotype (SASP). The homing of abundant circulating CMV-specific CD8+ T cells to such inflamed tissues could fuel a further feedback loop of activation, proliferation, and telomere attrition. Therefore, not only are dysfunctional immune cells indirectly contributing to senescent cell accumulation, but are themselves progressing towards senescence, reinforcing a vicious cycle that may be a key factor in "premature aging" of persons living with HIV and unhealthy aging in others.

If CMV infection is a major factor in shifting the adaptive immune system towards chronic senescence, the most dramatic effects should be revealed in the context of HIV infection, where increased chronic inflammation and exaggerated anti-CMV immune responses may optimally promote progression of age-independent chronic immunosenescence. Within this setting, CMV infection is associated with CD8+ T-cell progression towards cellular senescence, increased inflammation, and greater risk of age-related morbidities. This may represent acceleration of the same effects that CMV infection produces in old elderly individuals who develop an immune risk profile with its connotations for immunosenescence, unhealthy aging and mortality. Extensive proliferation and oligoclonal dominance of CMV-specific CD8+ T cells are the hallmarks and potentially drivers of these associations.

Researchers have succeeded in restoring mobility and sensation of touch in stroke-afflicted rats by reprogramming human skin cells to become nerve cells, which were then transplanted into the rats' brains. Several previous studies have shown that it is possible to transplant nerve cells derived from human stem cells or from reprogrammed cells into brains of rats afflicted by stroke. However, it was not known whether the transplanted cells can form connections correctly in the rat brain in a way that restores normal movement and feeling.

"We have used tracking techniques, electron microscopy, and other methods, such as light to switch off activity in the transplanted cells, as a way to show that they really have connected correctly in the damaged nerve circuits. We have been able to see that the fibres from the transplanted cells have grown to the other side of the brain, the side where we did not transplant any cells, and created connections. No previous study has shown this. It is remarkable to find that it is actually possible to repair a stroke-damaged brain and recreate nerve connections that have been lost. The study kindles hope that in the future it could be possible to replace dead nerve cells with new healthy nerve cells also in stroke patients, even though there is a long way to go before achieving that."

Stem cell transplantation can improve behavioral recovery after stroke in animal models but whether stem cell-derived neurons become functionally integrated into stroke-injured brain circuitry is poorly understood. Here we show that intracortically grafted human induced pluripotent stem (iPS) cell-derived cortical neurons send widespread axonal projections to both hemispheres of rats with ischemic lesions in the cerebral cortex. We find that at 6 months after transplantation, host neurons in the contralateral somatosensory cortex receive monosynaptic inputs from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their terminals form excitatory, glutamatergic synapses on host cortical neurons.

We show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does not recreate the impairment, indicating that its reversal is not due to neuronal activity in the graft. However, we find bilateral decrease of motor performance in the cylinder test after light-induced inhibition of either grafted or endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure of their axons to light on the contralateral side.

Our data indicate that activity in the grafted neurons, probably mediated through transcallosal connections to the contralateral hemisphere, is involved in maintaining normal motor function. This is an example of functional integration of efferent projections from grafted neurons into the stroke-affected brain's neural circuitry, which raises the possibility that such repair might be achievable also in humans affected by stroke.

The nature of the selection factors underlying the evolution of aging remains controversial. Many specialists in evolutionary gerontology support a set of ideas called the "evolutionary theory of aging". This theory is based on the idea that the selection efficiency decreases with age. It is also assumed that vitality and fertility are high in youth at the cost of reduced fitness at later ages. An alternative view is that programmed aging and death may be favored by some kind of selection.

A theoretical experiment called the "Fable about Fox and Hares" has been suggested. Two young hares differing "intellectually" have equal chances to escape from a fox since both hares are running faster than a fox. However, with age, the clever hare acquires some advantage, which becomes of crucial importance when the running speed of hares lowers to that of a fox. Now, the clever hare has a better chance to escape and, hence, to produce clever leverets than the stupid hare. Such an effect becomes possible due to age-dependent lowering of the running speed as a result of the operation of an aging program. This will facilitate the selection for cleverness.

The evolutionary changes in humans compared to other primates have the following distinguishing characteristics: large brain, exceptionally large life span, high paternal investment in offspring, and the role of older individuals as helpers in upbringing the children. The large brain is associated with a change in psychological characteristics: enhanced learning and cognition. Even human sleep is shorter, deeper, and has more rapid eye movement phases than that in other primates. Supposedly, the selection pressure in the direction of the reduction in sleep duration and its "quality" improvement were activated in the early stages of human evolution due to the change in the ecological niche and the development of overnight stays on the ground and not in the tree branches.

The evolution of these life history characteristics and extremely high intelligence was probably related to some degree to the dietary transition to high-quality, solid and hard-to-get food resources. In humans, technical progress leads to a sharp decrease in infant mortality and an increase in life expectancy, especially in comparison to wild chimpanzees. Despite the huge variation in the life span of various human populations, starting with preagricultural tribes and ending with the urban population in the developed countries, the differences between their survival curves are still smaller than those between the preagricultural human populations and the chimpanzees living in the wild. This relationship can be explained by the fact that neoteny prolongs life span and health span.

The change in survival curves of humans compared to chimpanzees occurs for two reasons: neoteny and very rapid technical progress. An analysis of time scales and survival curves allows us to separate these two causes. Thus, the evolution of neoteny requiring much more time may be responsible for the difference in the mortality curves of chimpanzees and hunter-gatherers, while technical progress is responsible for the great differences in the mortality curves of hunter-gatherers and Swedish individuals in the 20th century.

In recent years, replication stress (RS) has been acknowledged as an important source of endogenous DNA damage. RS is a type of DNA damage that occurs when obstacles to replication lead to an accumulation of single stranded DNA (ssDNA) at stalled replication forks, which is recognized by ssDNA binding protein RPA. This initiates a signaling cascade involving Ataxia Telangiectasia and Rad3-related (ATR) kinase and CHK1 which promotes DNA repair, cell cycle arrest, and apoptosis.

Similar to other types of DNA damage, RS has been linked to aging. For instance, aged hematopoietic stem cells (HSCs) exhibit increased levels of RS compared to young HSCs. In addition, mutations in the ATR gene cause Seckel syndrome in humans, which is characterized by progeria, growth retardation, microcephaly, mental retardation, and dwarfism. The involvement of RS in premature aging has also been shown experimentally with a mouse model for Seckel syndrome. ATR-Seckel mice exhibit a phenotype similar to that of human patients, which is further aggravated in combination with several cancer-driving mutations such as the Myc oncogene or the absence of the tumor suppressor p53. ATR-Seckel mice show high levels of RS during embryonic development, accelerated aging in adult life and early lethality.

Interestingly, mice harbouring extra alleles of Chk1 (Chk1Tg) or of the ribonucleotide reductase (RNR) regulatory subunit Rrm2 (Rrm2Tg), which is a limiting factor for dNTP production, improved the lifespan and alleviated the progeroid phenotype of ATR mutant mice. These Chk1 and Rrm2 transgenic mice carry bacterial artificial chromosome (BAC) alleles of the respective genes, including exons and introns, under their own endogenous promoters. This strategy provides supraphysiological levels of CHK1 and RRM2 while preventing overexpression in tissues where these genes are normally not expressed, and was proven successful with the Trp53 BAC-transgenic mouse mode.

Collectively, these studies suggested that RS might have important implications in mammalian aging. However, the effect of Chk1 and Rrm2 expression levels on normal aging, in mice with physiological levels of ATR, remains to be elucidated. In the current study, we investigated the effect of supraphysiological levels of CHK1 and RRM2, which confer extra protection against RS, on normal aging. We utilized cohorts of wild type, Chk1Tg, Rrm2Tg and Chk1Tg;Rrm2Tg mice to assess tumor-free survival of these mice. We found no differences in survival between the genotypes and all mice exhibited similar signs of aging. Thus, supraphysiological levels of CHK1 and RRM2 do not affect normal aging in mice.

The PESA ('Progression of early subclinical atherosclerosis') study has been monitoring 4200 healthy middle-aged men and women with noninvasive imaging technology and omics biomarkers for more than 10 years. The use of noninvasive imaging technologies "allows us to identify the progression of the disease earlier than is possible with classical markers, such as the presence of coronary calcium detected by computed tomography (CT), thus allowing us to identify individuals at higher risk who could benefit from early intervention. The results show that ultrasound of the peripheral arteries is a more efficient method for detecting atherosclerosis progression than the study of coronary calcium by CT."

Atherosclerosis is characterized by the accumulation of fatty deposits in the artery walls. The disease is normally detected at an advanced stage, when it has already caused clinical events such as a heart attack or stroke. Treatment of the disease at this symptomatic stage is of limited effectiveness, and most patients experience a decline in quality of life. The treatment of these patients, moreover, places a significant burden on health care resources.

"This study is the first to analyze the progression of atherosclerosis at frequent intervals. The previous view was that the disease progressed very slowly throughout life. However, the new results show that the disease progressed very rapidly in 40% of the individuals analyzed. Future data from the PESA study will show whether this progression is associated with subsequent cardiovascular events. Until now, the speed of atherosclerosis progression has not been a factor in assessing individual risk."

"The key finding of the study is that over a short follow-up of just 3 years, 40% of individuals aged between 40 and 50 years showed major progression of atherosclerosis in distinct locations, including the carotid, femoral, and coronary arteries. This rapid disease progression could make these individuals more vulnerable to developing symptoms or having clinical events such as a heart attack or stroke." The researchers conclude that the findings, while they await validation from the occurrence of events in the PESA cohort in the future, will be of great value in determining strategies to stall the epidemic of cardiovascular disease.

The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid.

This cross-sectional study included screening data in the A4 Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET, clinically normal, and cognitively unimpaired.

Amyloid PET results were acquired for 4486 participants (71.29 ± 4.67 years; 2647 women), with 1323 (29.5%) classified as amyloid-β (Aβ)+. Aβ+ participants were slightly older than Aβ-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ- [68%]) and at least 1 APOE ε4 allele (2602 Aβ+ [58%] vs 1122 Aβ- [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index.

In conclusion, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer's continuum.

Researchers looked at 19 elderly patients, all above the age of 75, and measured whether they suffered from frailty through three clinical analysis tests - the Edmonton frail scale (EFS), the Montreal cognition assessment (MoCA-J), and the Timed Up and Go Test (TUG). "Both the EFS and the MoCA-J gave us an indication of the individuals cognitive function, whereas the TUG allowed us to assess their motor ability. Between them, they also showed health status, mood, short-term memory, and other indications, so they gave us a clear idea of who suffered from the disorder." By using these three tests, the researchers found that nine out of the 19 individuals fit into the category of being frail whereas the other ten did not, however some still did suffer from cognitive impairment or hypomobility, a syndrome which hinders movement.

Next, the researchers took blood samples from the 19 patients and had a close look at the metabolites - small molecules of amino acids, sugars, nucleotides, and more that make up our blood. They tested 131 metabolites and found that 22 of them correlated with frailty, cognitive impairment and hypomobility. Patients who suffered from these disorders tended to have lower levels of most of these metabolites. The 22 metabolites identified included antioxidant metabolites, amino acids and muscle or nitrogen related metabolites. Fifteen of them correlated with frailty, six indicated cognitive impairment and twelve indicated hypomobility. The metabolites that correlated with frailty overlapped with five of those that indicated cognitive impairment and six that indicated hypomobility.

These metabolites include some of the aging markers in healthy people reported by the same group in 2016. This suggests that the severity of biological aging, which varies between individuals, could be monitored from an early stage of old age by measuring blood biomarkers. The research indicates that frailty has a distinct metabolomic profile when compared to other age-related disorders. By demonstrating a link between these metabolites and the symptoms of the disorder, these findings could lead to a different approach to diagnosing and treating frailty.

The link between mitochondrial dysfunction and atherosclerosis has been the subject of extensive research. A model that could link the mitochondrial DNA (mtDNA) mutation-induced mitochondrial dysfunction and deficient autophagy may help understanding of the importance of these events in the age-related nature of inflammation and identifying potential points of therapeutic intervention. Based on the available data, we propose a plausible mechanism, according to which, phagocytosis stimulation by circulating large associates of modified LDL activate the pro-inflammatory response of the innate immune system.

According to this hypothesis, atherogenic modified LDL circulating in the blood of atherosclerotic patients induces lipid accumulation in the arterial wall cells. Modified LDL particles form self-associates that penetrate the cell by nonspecific phagocytosis, stimulation of which by LDL associates activates the pro-inflammatory response of macrophages in the form of secretion of inflammatory cytokines. Secretion of cytokines leads to increased accumulation of intracellular lipids. If the innate immunity functions normally, the pro-inflammatory reaction resolves rather quickly and further lipid accumulation does not occur. However, when macrophages contain mtDNA mutations, the pro-inflammatory response does not arrest, but rather intensifies with each repeated pro-inflammatory stimulation. Local inflammation in the vascular wall becomes chronic and accompanied by uncontrolled lipid accumulation giving rise to an atherosclerotic lesion.

Another intriguing possibility is that cells may recognize the dysfunctional mitochondrion as a pathogen that presents foreign epitopes, therefore triggering the immune response. This may be a consequence of the bacterial origin of mitochondria, due to which defective mitochondria could be recognized by immune cells as pathogens triggering the innate immunity response.

The proposed concept allows speculation that atherogenesis is due to two errors made by the cell of the arterial wall. The first one is that the cell perceives the associates of modified LDL as a pathogen that is taken up by phagocytosis, which causes an inflammatory response and the accumulation of intracellular lipids, which in turn is a trigger of atherogenesis at the cellular level. The second is that due to mutations, the mitochondria becomes dysfunctional and due to a defect in mitophagy, the cell cannot free itself from this mitochondrion and perceives it as a bacterium-like pathogen. This triggers an ongoing inflammatory signaling that may lead to inflammasome activation.

Accumulating data demonstrate that a ketogenic diet elevates the levels of β-hydroxybutyrate (β-HB), improving many age-related diseases. Indeed, β-HB appears to act as a regulator of cellular signaling via numerous pathways in various cellular organelles in a manner that is independent of nicotinamide adenine dinucleotide (NAD) levels. Reports have verified that β-HB controls many cellular signals via its function as a ligand, regulates gene expression, inhibits or activates protein functions, and plays a role in neuronal functions. Thus, determination of the molecular targets of β-HB will provide a better understanding of how calorie restriction or a ketogenic diet improves age-related disease symptoms. Stemming from the current evidence, investigation of the detailed molecular capacity of β-HB will provide new opportunities for its application as a therapeutic target for the treatment or prevention of human diseases.

Approaches to increase circulating β-HB by dietary manipulation or ingestion of supplements have been examined via four different routes: a ketogenic diet, calorie restriction, ketone ester (KE) administration, and sodium-glucose transport protein 2 (SGLT2) inhibition. The ketogenic diet, calorie restriction, and SGLT2 inhibition induce ketogenesis in the liver through lipolysis. In particular, SGLT2 inhibition decreases insulin secretion from β cells, resulting in lipolysis in adipose tissues, regulation of ketone body reabsorption in the kidney, and increased β-HB. KEs are hydrolyzed by nonspecific gut esterases in the small intestine and liberate β-HB and (R)-1,3-butanediol, thus increasing the level of β-HB in the circulation.

β-HB supplementation extends the lifespan of C. elegans by 20% through the DAF-16/FOXO and SKN-1/Nrf pathways and the regulation of aging and longevity. In mammals, β-HB decreases the senescence-associated secretory phenotype (SASP) and the senescence of vascular cells. Moreover, the ketogenic diet significantly extended the median lifespan of mice and resulted in the preservation of the physical function of aged mice. Thus, β-HB and ketogenic diets can be considered important mediators with regenerative potential that also have the capacity to retard aging-associated phenotypes.

Since individual differences make it difficult to control the optimal circulating β-HB levels by calorie restriction or a ketogenic diet, it is necessary to develop adjustable treatment options, such as KE administration. As abrupt changes in circulating β-HB may disrupt energy homeostasis, the chiral enantiomer s-β-HB may offer a potential option for therapeutics, as this molecule cannot be used as an alternative energy metabolite. Furthermore, s-β-HB is not consumed by the physiological system, and the half-life of s-β-HB in circulation is longer than that of β-HB. As β-HB alleviates various age-associated disease symptoms and aging phenotypes via diverse and yet unknown molecular mechanisms, evaluation of β-HB and/or s-β-HB as a therapeutic agent is an important approach for the treatment of the aging population.

Putting together a conclusive theory of aging has been difficult due to the inability to properly quantify and define aging. Consequently, the efficacy of various geroprotective interventions remains subject to controversy. Without general agreement as to what constitutes aging and biological age (BA), and how to measure their progression, conclusions on the benefits of particular therapies are likely to be biased. Meanwhile, the very existence of a reliable way to measure BA remains under question.

It is possible that aging has no distinct genetic signature and is in essence a multitude of simultaneous damage accumulation processes. If that is true, BA as a concept is unlikely to be a property of objective reality but should be treated as an artificial construct. If there is indeed no singular process behind all the manifestations of aging, measuring BA is infinitely harder than in the case of single-source aging. It would require either (a) finding a common denominator for the majority of aging-related processes or (b) arbitrarily weighing all such processes according to their perceived importance to form the final "age score".

The problem of multiple aging processes is further confounded by individual variability. There are indications that people age according to different trends that can be grouped into several "ageotypes" defined by the hierarchical clustering of their biomarkers. Moreover, the fluidity of individual ageotypes can cause unstable performance of an aging score within any singular individual. Nonetheless, a reliable and universally agreed upon way to quantify BA is a necessity for modern biogerontology. Most importantly, it would enable flexible experimental designs and in many cases would remove the need to follow up human subjects for decades to evaluate the benefits of a geroprotective intervention. Moreover, it could be used as a criterion to test the relevance of specific diseases, pathways or processes in the context of aging research.

Despite advances in our understanding of cellular and molecular neuroinflammatory mechanisms underlying adverse outcomes following injury, approved therapeutics that target this pathological process are lacking. Although there have been significant advances in the medical management of patients with acute brain injuries, there is a clear and urgent need for interventions that improve neurologic recovery and outcomes. To address this medical need, we developed a small-molecule drug candidate, MW01-6-189WH, hereafter called MW189. MW189 was developed as a selective suppressor of injury- and disease-induced glial proinflammatory cytokine overproduction associated with destructive glial inflammation/synaptic dysfunction cycles, and their long-term neurotoxic effects.

MW189 is efficacious in vivo in animal models of acute brain injury, in which upregulation of proinflammatory molecules is implicated in disease progression. By attenuating the inflammatory responses of overstimulated glia, MW189 may limit the pathological progression and neurocognitive dysfunction that complicate a variety of central nervous system disturbances.

We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results

A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury.

Frailty, a consequence of the interaction of the aging process and certain chronic diseases, compromises functional outcomes in the elderly and substantially increases their risk for developing disabilities and other adverse outcomes. Frailty follows from the combination of several impaired physiological mechanisms that affect multiple organs and systems. And, though frailty and the age-related loss of muscle mass and strength known as sarcopenia are related, they are two different conditions. Thus, strategies to preserve or improve functional status should consider systemic function in addition to muscle conditioning.

Physical activity/exercise is considered one of the main strategies to counteract frailty-related physical impairment in the elderly. Exercise reduces age-related oxidative damage and chronic inflammation, increases autophagy, and improves mitochondrial function, myokine profile, insulin-like growth factor-1 (IGF-1) signaling pathway, and insulin sensitivity. Exercise interventions target resistance (strength and power), aerobic, balance, and flexibility work. Each type improves different aspects of physical functioning, though they could be combined according to need and prescribed as a multicomponent intervention. Therefore, exercise intervention programs should be prescribed based on an individual's physical functioning and adapted to the ensuing response.

Research has sought to ascertain the genetic program and prodrome underlying the development and phenotype of senescent cells. Expedited by recent advances in genomic and transcriptomic sequencing, alongside high-throughput genetic screens, a wealth of publicly available data now exists which has furthered the understanding of senescence regulation. Unfortunately, despite our increasing knowledge of cellular senescence (CS), determining whether a cell has senesced is not clear-cut.

Common senescence markers used to identify CS in vitro and in vivo include senescence-associated β-galactosidase (SA-β-gal) and p16INK4A (p16). However, β-galactosidase activity has been detected in other cell types such as macrophages, osteoclasts, and cells undergoing autophagy. Furthermore, some forms of senescence are not associated with p16 expression, while p16 has been detected in non-senescent cells. As such, there are now over 200 genes implicated in CS in humans alone.

Biological networks can be built using protein interaction and gene co-expression data. Here, we present the network of proteins and genes co-expressed with the CellAge senescence genes. Assaying the networks, we find links between senescence and immune system functions and find genes highly connected to CellAge genes under the assumption that a guilt-by-association approach will reveal genes with similar functions. In this study, we look at the broad context of CS genes - their association with aging and aging-related diseases, functional enrichment, evolutionary conservation, and topological parameters within biological networks - to further our understanding of the impact of CS in aging and diseases. Using our networks, we generate a list of potential novel CS regulators and experimentally validate 26 genes using siRNAs, identifying 13 new senescence inhibitors.

Proteins are the building blocks of life as they are not only the structural constituents of the living organisms but also a final functional molecule governing most of the biological functions. The proteins undergo alterations by spontaneous non-enzymatic Degenerative Protein Modifications (DPMs) including oxidation, deamidation, carbamylation, carbonylation, glycation, etc. The DPMs change protein charge state, hydrophobicity, and three-dimensional structure that influence functional activities and induce aggregation.

These protein modifications and accumulation of modified proteins are allied to aging and the development of age-associated pathologies like neurodegenerative diseases. DPMs like spontaneous protein deamidation characterized by the modification of glutaminyl and asparaginyl residues were hypothesized as a molecular timer of biological events including protein turn over, development and aging. Protein deamidation will progressively disrupt structural integrity of the protein and alter biological activity. Other DPMs including glycation, advanced glycation end products, oxidation, carbonylation, carbamylation, etc., impart deleterious structural and functional changes in proteins and impair their normal function.

Hypoxia, a condition where oxygen supply to tissue is inadequate, induces free radical generation leading to oxidative protein modifications and tissue damage. Oxygen supply also acts as a modulator of aging processes. The cerebrovascular disorders and hypoxia-ischemia injuries in the brain are projected as a primary cause of protein pathologies that leads to cognitive impairment and dementia. In short, hypoxia-ischemia injury in the brain persuades DPMs that can lead to aging, age-associated diseases and neurodegeneration.