Partial inhibition of complex I with small molecules emerged as a promising strategy to induce beneficial mitochondrial induced stress response. Complex I inhibitors are in clinical trials for various human conditions, including type 2 diabetes, cancers, metabolic disorder, obesity, inflammatory and infectious diseases. Only metformin, resveratrol, berberine, and epigallocatechin-3-gallate were trialed in a limited number of studies for neurodegenerative diseases, including Alzheimer's disease (AD). Metformin improved cognitive function in patients with amnestic MCI, while resveratrol, berberine and epigallocatechin-3-gallate did not show statistically significant improvements in cognitive performance in patients with AD, Huntington's disease, or MCI. While all four complex I inhibitors penetrate the blood-brain barrier (BBB), the therapeutic effect of resveratrol, berberine and epigallocatechin-3-gallate was limited, probably due to a poor stability, short half-life, and a very low bioavailability in contrast to metformin. Therefore, modifications of current complex I inhibitors or the development of new small molecules with improved drug-like properties and bioavailability are needed to increase therapeutic efficacy for neurodegenerative diseases.

We recently identified a small molecule tricyclic pyrone compound (CP2) that penetrates the BBB and accumulates in mitochondria where it mildly inhibits the activity of complex I. CP2 is bioavailable, has low toxicity in vitro and in vivo, and has good drug-like properties and safety profile. CP2 increased mitochondrial respiratory control ratio and reduced proton leak, suggesting better coupling efficiency of the neuronal electron transport chain (ETC), greater bioenergetic reserve, and enhanced ability to withstand stress. In vivo efficacy of chronic CP2 administration was examined in independent cohorts of male and female mouse models of AD. In all studies, chronic CP2 treatment did not induce toxicity or affect development. Remarkably, in all treatment groups, CP2 improved energy homeostasis in the brain and periphery (glucose uptake and utilization, glucose tolerance, and insulin resistance), synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis (reduced amyloid-β and phosphorylated Tau levels), and reduced oxidative stress and inflammation in the brain and periphery, ultimately blocking the ongoing neurodegeneration.

In conclusion, we summarized here evidence for a novel therapeutic approach to exploit the incredible ability of mitochondria to engage multifaceted neuroprotective stress response triggered by partial complex I inhibition. This approach promises relief for multiple human conditions, and to promote healthy aging to delay the onset of neurogenerative diseases, AD in particular, where age is the greatest risk factor. There is a mounting body of evidence generated in model organisms and humans in support of the safety of chronic application of complex I inhibitors. However, a better understanding of the molecular mechanisms is required to establish safety in translation to humans, including the development of biomarkers that inform on mitochondrial function and the capacity to induce the beneficial stress response. Further therapeutic developments should produce selective and specific complex I inhibitors capable of penetrating the BBB with excellent safety profile.

Reproductive aging is defined as the age-related loss of fertility due to increasing damage to the reproductive and other systems. Oocytes themselves accumulate damage in an age-related manner and deteriorate to the point where they are non-functional. In human, females this occurs at a relatively early age, before the onset of aging in other organs and tissues. In our era of increased rate of delayed childbearing, it is becoming crucial to understand the mechanisms underlying the compromised quality of oocytes with age.

Changes in epigenetic regulation of gene expression and chromosome structure have been recognized as contributors to aging, and epigenetic changes during aging have been listed among the "hallmarks of aging". The loss of heterochromatin histone marks has been associated with the aging process in many systems and tissues. It was shown that epigenetic changes occur in mouse oocytes of advanced maternal age, at ages where aneuploidy is considerable. However, the mechanisms that are altered by these changes, and the ways they affect the different aspects of oocyte aging are yet to be explored. The consequences of heterochromatin de-regulation in aging may be related to the activated transcription of transposable elements (TE) in the genome, and their subsequent effect on genome stability and cellular integrity. This was shown to occur in several organisms and systems. Currently, it is unclear whether TE are activated in older oocytes, and whether, and when exactly, TE expression is involved in oocyte aging and epigenetics.

In this work, we study the role of heterochromatin loss in the aging of oocytes. We show that heterochromatin loss in oocytes can be detected at an age of 9 months in mice, when low aneuploidy rates are present, but a decrease in oocyte quality is evident, as previously reported. We show that these changes are characterized by the loss of repressive histone marks, elevation of specific retrotransposon mRNA transcription, elevated processing of repeated sequences and retrotransposons, and increased activation of the DNA repair machinery. Treatment of oocytes with chemical compounds that inhibit heterochromatin formation can mimic the effect of aging and cause a decrease in oocyte maturation rates and elevation in L1 retrotransposon activity and DNA damage.

Importantly, we find that the effect of heterochromatin loss and L1 retrotransposon activity on oocyte maturation with age is partially reversible through treatment of oocytes with AZT, a SIRT1 activating molecule-SRT-1720, or overexpression of Sirt1 or Ezh2 in older oocytes. Treatment with AZT does not prevent epigenetic failure in older oocytes while the other interventions do. This fact demonstrates that the epigenetic effect is upstream to retrotransposon activation at this stage of the aging process.

α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans.

We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q).

We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence.

In summary, senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials.

In this review, we seek a novel strategy for establishing a rejuvenating microenvironment through senescent cells specific reprogramming. We suggest that partial reprogramming can produce a secretory phenotype that facilitates cellular rejuvenation. This strategy is desired for specific partial reprogramming under control to avoid tumour risk and organ failure due to loss of cellular identity. It also alleviates the chronic inflammatory state associated with ageing and secondary senescence in adjacent cells by improving the senescence-associated secretory phenotype (SASP).

Senescence-specific phenotypes are manifested by increased expression of senescence-associated genes and altered metabolic state, while cell cycle (cell cycle withdrawal) and protein synthesis also appear to be characteristically altered. Of these, the SASP is an essential component of the senescence microenvironment. The multiple cytokines, enzymes, and extracellular vesicles (EVs) that make up the SASP can interact with young cells through the senescence microenvironment, a balance that generally promotes senescence. Still, the rejuvenating microenvironment of immature cells can also improve the metabolic state of senescent cells at the tissue level and thus break the senescence signature within senescent cells through the remodelling of protein synthesis and gene expression. It is possible that the vicious cycle of senescence within senescent cells can be broken through the remodelling of protein synthesis and gene expression patterns.

This may be an opportunity left by evolution to combat senescence with controlled reprogramming of local tissues (based on the Yamanaka factors, which essentially create a persistent young environment in a controlled manner), in turn, radically improving the overall senescence homeostasis of senescent cells through metabolic reprogramming and epigenetic remodelling, and this deadlock-breaking anti-ageing strategy is autonomously regulated by the ageing microenvironment, depending on the degree of senescence (the more the microenvironment is inclined to senescence, the easier the local reprogramming, metabolic reprogramming, and epigenetic remodelling). In summary, the phenomena we expect to see in future research and clinical translation are as follows: As rejuvenation becomes more pronounced, local reprogramming loses the promotion from SASP and combines with a controlled induction system to avoid tumours and loss of cellular function.

Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co-occurrence of age-related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non-random associations between age-related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data.

Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway, and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age-related diseases. Mechanisms of aging hence contribute both together and individually to age-related disease co-occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity.

Recent work has shown that it is possible to prevent or even reverse the dysregulation of oxidative stress, autophagy, and the occurrence of senescence using a new class of drugs called geroprotectors. Geroprotectors are drugs that delay or reverse ageing processes and in doing so target the major risk factors for age-related diseases. They promise to promote health span of more than one organ system at the same time in animal models. Studies in model organisms or retrospective studies in patients show that they can ameliorate tissue dysfunction and reduce the onset and severity of many diseases. Over 200 compounds have been classified as geroprotectors, each reported to slow ageing and/or extend lifespan in a variety of organisms.

Such drugs could have distinct advantages over present treatments in osteoporosis (OP) and offer new opportunities for osteoarthritis (OA) due to the fact that they may be able to prevent both OP and OA and their co-morbidities. However, the effects of geroprotectors on skeletal health have received little attention compared to other organ systems with the assumption that these drugs will work equally well for all tissues. Here we review the evidence available to address whether geroprotectors have potential for the care of skeletal age-related diseases and their co-morbidities. We focus on drugs with a good safety profile, which have been shown to target ageing pathways, extend the lifespan and healthspan in animal models and have some evidence of improving health in humans by demonstrating protection from multiple-age-related diseases and for which there are well designed studies in animal models of OP and OA or clinical data available.

Geroprotectors potentially have additional benefits to treat OA and OP and their co-morbidities. However, few studies focus on skeletal health despite their burden of disease. Only one study with the combination of senolytics dasatinib and quercetin shows signs of improvement in a model of bone loss and no improvement has been demonstrated so far in aged models of OA. These studies highlight that extension of lifespan cannot be considered a surrogate marker for extension of health span in all tissues and thorough studies in aged models of OP and OA are required to assess the real benefit of geroprotectors to improve skeletal health.

A meta-analysis of 15 studies involving nearly 50,000 people from four continents offers new insights into identifying the amount of daily walking steps that will optimally improve adults' health and longevity - and whether the number of steps is different for people of different ages. Taking more steps a day helps lower the risk of premature death.

More specifically, for adults 60 and older, the risk of premature death leveled off at about 6,000-8,000 steps per day, meaning that more steps than that provided no additional benefit for longevity. Adults younger than 60 saw the risk of premature death stabilize at about 8,000-10,000 steps per day. "So, what we saw was this incremental reduction in risk as steps increase, until it levels off. And the leveling occurred at different step values for older versus younger adults."

Interestingly, the research found no definitive association with walking speed, beyond the total number of steps per day. Getting in your steps - regardless of the pace at which you walked them - was the link to a lower risk of death. The new research supports and expands findings from another study, which found that walking at least 7,000 steps a day reduced middle-aged people's risk of premature death.

Cellular senescence is a state of stable cell-cycle arrest despite continued metabolic activity, which usually occurs in response to many endogenous and exogenous stresses during aging processes. Historically, senescence was first identified half a century ago, with the discovery that human diploid fibroblasts displayed a finite capacity for cell division because of telomere shortening (replicative senescence). Conversely, the telomere length-independent senescence was then observed in many aged or damaged tissues. Such stress-induced premature senescence (SIPS) can be triggered by distinctive stressful stimuli, including persistent DNA damage, oncogene activation, oxidative stress, and mitochondrial dysfunction in the cardiovascular system.

Eminently characterized by a proliferation arrest, the senescent cells are differed from other non-dividing cells (such as quiescent cells) with specific morphological and functional features. Growing evidences demonstrated that the senescent cardiovascular cells, including endothelial cells, vascular smooth muscle cells, fibroblast cells, cardiomyocytes, T cells and et al., were accumulated in the culprit lesions of cardiovascular system and act to improve or exacerbate the onset and outcome of cardiovascular diseases. While cellular senescence imposes an important role in suppressing tumorigenesis. There is strong evidence that cellular senescence also participates in the progression of heart regeneration, cardiac remodeling, atherosclerosis, and heart failure.

In this review, we first discuss the mechanisms and the features underlying cellular senescence. Then, we summarize the different types of senescent cells that present in cardiovascular systems and describe the pathophysiological implications of cellular senescence in cardiovascular disease. Moreover, we highlight the role of SIRT1 and mTOR in regulating senescence during age-related cardiovascular diseases. Finally, we focus on the emerging pro-senescent and anti-senescent therapies and discuss their therapeutic potential for cardiovascular diseases.

Epidemiological studies show a strong independent association between age-related hearing loss (ARHL) and Alzheimer's disease (AD). Actually, recent data link 9% of sporadic AD to hearing loss starting at mid-life. Thus, ARHL emerges as the main preventable risk factor of AD, at least in this life period, even with causal implications. Comorbidity between ARHL and AD will further aggravate the condition of the patients, multiplying health, social, economic, and sanitary impact. In sum, epidemiological data link ARHL with cognitive impairment and dementias, in particular AD, pointing to dynamic association between these two neurodegenerative conditions. Besides ARHL contributing to the pathogenesis of AD, the converse may also be the case. However, at present, the biological or mechanistic foundations of such interplay are unknown.

Several hypotheses/mechanisms have been put forth. These include existence of shared underlying pathologies, such as those of vascular origin; diminished auditory input that directly triggers brain atrophy as an expression of the complex chain of cellular events leading to dementia; overload of cognitive resources, diverted to process diminished auditory input; existence of amyloid plaques (AP), intraneuronal neurofibrillary tangles (NFT) and cytoskeletal pathology in the cochlea, dorsal cochlear nucleus, superior olive, central nucleus of the inferior colliculus, medial geniculate body, primary auditory cortex and association area of the auditory cortex. These or another related hypothesis/mechanism do not exclude each other mutually. Whether such interplay is unidirectional from ARHL to AD, or bidirectional is also unknown. The challenge of testing such intricate and open-end hypotheses scenery, is the complexity and multiplicity of factors involved in the genesis and development of both neurodegenerative conditions.

Frailty and related oxidative stress have recently drawn considerable attention. In this review, we discuss the possibility that the oxidative stress linked to frailty, could be, at least in part, primarily involved in the interplay between ARHL and AD.

There have been advances in healthcare over recent decades that mean many people with chronic health conditions are living longer. In the new study, researchers wanted to determine whether this extension to life involves an increase in years with or without disability. The team analyzed data from two large population-based studies of people aged 65 or over in England. The studies, the Cognitive Function and Aging Studies (CFAS I and II) involved baseline interviews with 7,635 people in 1991-1993 and with 7,762 people in 2008-2011, with two years of follow-up in each case.

For both healthy people and those with health conditions, the average years of disability-free life expectancy (DFLE) increased from 1991 to 2011. Overall, men gained 4.6 years in life expectancy and 3.7 years in DFLE. Men with conditions including arthritis, coronary heart disease, stroke, and diabetes gained more years in DFLE than years with disability. The greatest improvements in DFLE in men were seen for those with respiratory difficulties and those living post-stroke. Between 1991 and 2011, women experienced an increase in life expectancy at age 65 years of 2.1 years, and an increase in DFLE of 2.0 years. Similar to men, most improvement in life expectancy for women with long-term conditions was in disability-free years.

However, women with cognitive impairment experienced an increase in life expectancy with disability (1.6 years) without any improvement in DFLE. Men with cognitive impairment experienced only a small increase in DFLE (1.4 years) with an increase in life expectancy with disability that was comparable in magnitude (1.4 years). Therefore, at age 65, the percentage of remaining years of life which were spent disability-free decreased for men with cognitive impairment and women with cognitive impairment.

Osteoporosis is a frequent age-related disease that results from a dysregulation of the activities of osteoclasts and osteoblasts. As in other age-related diseases, research in the last decade has clearly provided evidence for a role of senescence in age-related osteoporosis. In pioneering work the expression of the senescent cell biomarker p16Ink4 was shown to increase in bone-derived B cells, T cells, myeloid cells, osteoprogenitors, osteoblasts, and osteocytes from young versus old male and female mice. Moreover, osteocytes and myeloid cells were identified as the cell populations with the most pronounced upregulation of senescence-associated secretory phenotype (SASP) factors within the bone environment.

Accumulation of senescent cells in the context of age-related and radiotherapy-related bone loss was since then confirmed by others, and was also shown in bone biopsy samples from older postmenopausal compared to younger premenopausal women. A causative role of senescent cells in mediating age-related bone loss was finally evidenced by pharmacological clearance of senescent cells in old mice or genetic clearance of senescent cells by inducible elimination of p16Ink-4a-expressing senescent cells using INK-ATTAC transgenic mice. The positive effect on bone microarchitecture and bone strength observed in these models after clearance of senescent cells was shown to be mediated partly by the elimination of senescent osteocytes. Moreover, increased bone formation by osteoblasts and a reduction in bone marrow adipose tissue was seen, and thereby supported a shift in bone marrow-derived mesenchymal stem cell (BMSC) differentiation from osteoblasts to adipocytes as mechanism of senescence mediated age-related bone loss

Taken together, a major focus in recent research has been on the role of senescence in BMSC proliferation and differentiation, and major progress has been made in elucidating potential regulators of senescence-mediated bone loss in age-related osteoporosis. This knowledge provides an important foundation for an in-depth understanding of the application of already existing senescence-based therapeutic options in the treatment of osteoporosis. Furthermore, by closing the gaps, in future, novel therapeutic options with a more specific and individualized approaches may arise.

In almost 3,000 participants of the Rhineland Study aged between 30 and 94 years, the retina was assessed using "spectral domain optical coherence tomography" (SD-OCT) - a technique that provides detailed images of the retina and its various layers. In addition, brain scans were performed by magnetic resonance imaging (MRI). The data were analyzed using sophisticated software algorithms. This allowed for automated identification and determination of thickness and volumes, of both the different retinal layers and the different structures of the brain. Next, researchers looked for associations between the volume of the retina and the volume of certain brain structures.

There was a close relation between layers of the inner retina and the white matter in the brain. The thinner these retinal layers, the smaller the volume of the brain's white matter. By contrast, sections of the outer retina were mainly associated with the gray matter of the cerebral cortex. In the brain's occipital lobe, where visual processing happens, these associations were particularly pronounced. And the researchers found further relationships. The thickness of different retinal layers correlated closely with the volume of the hippocampus. This is an area of the brain that plays a central role in memory and is often affected in dementia.

"Imaging of the retina using SD-OCT is relatively simple, non-invasive and inexpensive. The current results suggest that SD-OCT measurements of the retina could potentially serve as biomarkers for brain atrophy and to monitor progression of certain neurodegenerative diseases. Further population-based studies as well as studies in patient groups and over a longer period of time are now needed to verify these results in a clinical setting."

The presence of more than one mitochondrial DNA (mtDNA) genetic variant in the cell is called heteroplasmy. Although very rare, heteroplasmy sometimes occurs naturally as a result of mtDNA mutations and can cause several diseases. New therapeutic approaches proposed in recent years and aimed at preventing disease or treating infertility can generate a new form of heteroplasmy in people. "This new form of heteroplasmy, involving distinct non-mutated mtDNA variants, is produced when an individual's cells contain both the original recipient mtDNA and the donor mtDNA transferred during the intervention."

Researchers generated mice with a single nuclear genome but with all their cells simultaneously containing two distinct mtDNA variants. This mouse strain was fertile, and young animals showed no related disease. But long-term analysis over the full lifetime of these mice showed that the coexistence of two mtDNA variants in the same cell compromised mitochondrial function. "We observed that cells rejected the presence of two mitochondrial genomes, and most of them progressively eliminated one of the mtDNA variants. Surprisingly, however, major organs like the heart, lungs, and skeletal muscle were unable to do this."

Organs that could eliminate one of the mtDNA variants, like the liver, recovered their mitochondrial metabolism and cellular health, but those that could not progressively deteriorated as the animals aged. Thus the animals, which appeared healthy in their youth, in later life suffered from heart failure, pulmonary hypertension, loss of muscle mass, frailty, and premature death. The researchers conclude that the dangerous effects of mitochondrial therapeutic interventions identified in the new study show the need for caution in the selection of the donor mtDNA genotype.

Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of the damaged tissue or dead cells. DAMPs are (i) rapidly released following necrosis; (ii) produced by the activated immune cells via specialized secretion systems or by the endoplasmic reticulum (ER)-Golgi apparatus secretion pathway; (iii) known to activate the innate immune system by interacting with pattern-recognition receptors (PRRs), and thereby directly or indirectly promote adaptive immunity responses; (iv) inclined to contribute to the host's defense and pathological inflammatory responses in non-infectious diseases; and (v) responsible for restoring homeostasis by promoting the reconstruction of the tissue.

Accumulating evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, hyperglycemia, oxidative stress, ischemia, mechanical trauma, stress, environmental condition, and genetic defects during retinal development. Recent studies suggested that DAMPs that include extracellular matrix (ECM)-proteins are increased; this suggests a protective or pathogenic role in different retinal disorders. In retinal disorders DAMPs function through multiple specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs), and the NOD-like receptor (NLRs) family.

The diverse nature of the retinal cell types and their neuronal circuitry complicates our understanding of the cell-specific immune responses and the release of DAMPs in various retinal disorders. Therefore, future studies are warranted to identify the DAMPs involved in the molecular mechanisms of retinal diseases, employing single-cell or cell-specific proteomic signatures to identify/design or repurpose next generation therapeutics for retinal disorders.