Fight Aging! Newsletter, August 22nd 2022

Aging- and age-related diseases have been shown to be closely related to decreased NAD+ levels. In animal studies, the administration of intermediate NAD+ metabolites, such as nicotinamide (NAM), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR), has been shown to increase NAD+ concentrations, which helped improve the health and extend the lifespan of the experimental animals. Thus, the potential of intermediate NAD+ metabolites in improving tissue rejuvenation in humans has led to multiple clinical trials on NR and NMN.

The results of NR clinical trials have been reported. In these trials, NR (100-2000 mg/day) was administered to healthy participants or individuals with obesity for a maximum of 12 weeks. Most NR clinical trials have reported the safety of NR administration and the elevation of NAD+ or NAD+ -related metabolites in the blood. The most recent report showed that NR increases the fat-free body mass in participants with obesity, although no effect was observed on insulin sensitivity, mitochondrial function, and hepatic and intramyocellular lipid accumulation.

Recently, for the first time, the safety of single-day NMN oral administration was reported in humans. Moreover, while the drafting of this paper was underway, a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in 25 postmenopausal women with prediabetes was reported, in which NMN supplementation increased muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese. Furthermore, the effects of NMN supplementation combined with exercise training have been reported in healthy amateur runners aged 27-50 years. NMN dose-dependently increased the ventilatory threshold and improved aerobic capacity during exercise. However, evidence of the effects of human interventions with NMN remains limited for older adults.

Therefore, to elucidate the safety and efficacy of NMN administration in older adults, we conducted a placebo-controlled, randomized, double-blind, parallel-group study with the administration of 250 mg of NMN to 42 healthy men aged 65 years or more for 12 weeks. We demonstrated that NMN oral supplementation at 250 mg/day in healthy older men for 12 weeks was safe and well-tolerated and significantly increased the levels of NAD+ and NAD+-related metabolites in whole blood. Furthermore, NMN administration partly improved muscle performance, evaluated using gait speed and grip strength, in healthy older men. Conversely, no difference was observed in the indicators of vascular functions, such as assessed blood pressure and flow-mediated dilation. Chronic NMN supplementation did not affect the visceral or liver or spleen fat mass distribution. Likewise, NMN administration did not affect the homeostatic model assessment of insulin resistance (HOMA-IR), an indicator of hepatic insulin sensitivity in blood analysis. Adiponectin and interleukin 6 (IL-6), which are also related to insulin sensitivity, were unaffected by NMN administration. Lastly, the intervention exerted no observable effect on overall cognitive function.

Sepsis is an intricate, heterogeneous, and highly fatal syndrome, which is responsible for life-threatening organ dysfunction due to the immune regulation disorder. The third international consensus definition of sepsis and septic shock (Sepsis 3.0) recommended the sequential organ failure assessment (SOFA) to assess sepsis and hence predict the subsequent prognosis. While the old definitions of sepsis greatly emphasized infection, Sepsis 3.0 focused on the dysregulation of the body's response to infection and organ dysfunction. Furthermore, the organ damage scored by SOFA focuses on organs like lungs, heart, liver, kidneys, and brain. Surviving sepsis is associated with chronic, long-term consequences in host protective immunity. Additionally, researchers observed that most of the survivors suffered from issues like nervous system disturbances and cognitive dysfunction throughout their life span.

Since several similarities are found between immunosuppression after sepsis and immunosenescence, researchers hypothesized that these two factors might be associated with the progressive failure of immune functions. In sepsis, an increase in the number of myeloid-derived suppressor cells (MDSCs) was associated with the regulation of the function of other immune cells, and excessive inflammation was blocked. It has been suggested that MDSCs play a paradoxical role in sepsis: these cells may increase the production of proinflammatory cytokines during emergency myelogenesis and be also potently immunosuppressive. MDSCs may induce immunosenescence in the remodeled immune system. Therefore, we were interested in analyzing the effect of immunosenescence on sepsis, including the effect on the parenchymal organs. Here we review the possible relationship between septic injury-related organs and immunosenescence and analyze the possible mechanisms of immunosenescence after sepsis, which may shed some light on the delayed consequences of sepsis.

Cellular senescence, a complex cellular response to stress characterized by a halt of cell cycle progression, is one factor contributing to aging and age-associated diseases. It is believed that selective elimination of senescent cells can lead to rejuvenation of the aged organism and increase the healthspan, and as a result, clearance of senescent cells can serve as a therapeutic approach to combat many negative aspects of aging. The age-dependent accumulation of senescent cells is caused by age-related attenuated efficiency of the immune system and their higher resistance both to extrinsic and intrinsic pro-apoptotic stimuli, including oxidative stress. While the mechanisms driving senescence are well studied, understanding the mechanisms endowing these cells with increased survival capacity is limited.

The BCL-2 protein family plays a central role in cell death regulation by diverse mechanisms, including apoptosis and autophagy. This protein family, in addition to multidomain pro-apoptotic proteins Bax, Bak, and Bok and BH3-only proteins, also includes the anti-apoptotic proteins BCL-2, BCL-W, BCL-XL, MCL-1, and A1, and is intensively studied as a target for pharmacological intervention in cancer. Researchers have evaluated the contribution of individual members of the BCL-2 family and their combinations to the viability of senescent cells. They found that the increased presence of BCL-W and BCL-XL underlies senescent cell resistance to apoptosis and their combined inhibition induces the death of senescent cells. This mechanism is believed to be a basis for senolytic effects of BCL-2 inhibitors such as ABT-737 or ABT-263 (Navitoclax).

ABT-737 and ABT-263 both display a high affinity for BCL-2, BCL-XL, and BCL-W, but not A1, or MCL-1. In this study, we aimed to search for synergistic selective senolytic effects. We found that combining selective MCL-1 inhibitors with non-MCL1 BCL-2 inhibitors results in marked synergistic effects with higher sensitivity of senescent compared to proliferating cells. These findings indicate that a combination of drugs targeting different BCL-2 family members can benefit for senolytic therapies.

The elimination of senescent cells has emerged as a plausible therapeutic strategy for preventing, delaying, or alleviating multiple diseases and age-related dysfunction. Promising results of senolytics in preclinical models suggest therapeutic and preventive opportunities for delaying multimorbidity and increasing healthspan. A key priority should be the identification of reliable, sensitive and specific gerodiagnostics - biomarkers to quantify senescent cell abundance, the senescence-associated secretory phenotype (SASP), and senolysis as well as other pillars of aging.

Fundamental aging mechanisms can be grouped into so-called hallmarks or 'pillars' of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence. The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction and loss of resilience. The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others. For example, interventions that target cellular senescence tend to attenuate other fundamental aging mechanisms leading to reduced inflammation, attenuated exhaustion of progenitors, decreased fibrosis, alleviated mitochondrial dysfunction, and a partially restored microbiome in experimental animal models of aging and chronic diseases

Based on promising results in preclinical models, over 20 clinical trials of senolytic therapies are completed, ongoing or planned. Because side effects of senolytics in humans are not yet fully known, and to maximize benefit-risk ratios, the first clinical trials are underway in patients with serious health conditions, such as diabetic kidney disease, Alzheimer's disease, frailty and idiopathic pulmonary fibrosis (IPF). The first in-human trial of senolytics (dasatinib and quercetin, D + Q), the Hematopoietic Stem Cell Transplant Survivors Study, is still underway (NCT02652052; first patient dosed on 1 April 2016). The first senolytic clinical trial published was an open-label pilot study in which 14 patients with IPF were treated with intermittent D + Q on 3 days per week for 3 weeks. Results suggested that senolytics improved physical function in these frail patients. Furthermore, post hoc analysis of a study involving 20 patients with IPF showed that urine levels of the 'geroprotective' factor α-Klotho were higher after oral D + Q than before treatment. In an open-label phase 1 pilot study in 9 patients with diabetic kidney disease, a 3-day course of oral D + Q was sufficient to decrease adipose tissue senescent cell burden, inflammation, fibrosis and circulating SASP factors for at least 11 days after the last dose of senolytics, indicating target engagement and suggesting that an intermittent dosing regimen may be effective in humans.

These early data warrant evaluation in larger randomized, double-blind, placebo-controlled trials for senescence-associated disorders and diseases, some of which are underway

Rising life expectancy at older ages has raised concerns that the period of poor health and disability prior to death is growing. Research typically addresses this topic with the implicit assumption that advancing age is the main risk factor for declining health. However, the onset of several health conditions, including end-of-life depression and cognitive decline, is more closely linked to years of life remaining than years lived. Comparing the health of older adults who are the same proximity to death (for example, comparing all adults in their last year of life) may yield different insights than comparing adults who are the same age, but differing distances from death (for example, comparing all 70 year-olds).

In this paper, I examine trends and inequalities in aging from the perspective of time to death, rather than time since birth. I compare three indictors of health - self-rated health (SRH) and two self-reports of disability - in the last 6 years of life among adults dying at ages 65+ across time, sex, age, race, and educational attainment. SRH is a subjective and self-reported indicator of health. While the two disability measures are also self-reported, they serve as more objective assessments of requiring assistance. This study is the first to examine annual trends in SRH at the end of life, as well as the first to produce national estimates of end-of-life SRH for several subpopulations.

Despite concerns about expanding morbidity at the end of life, I find that the amount of time individuals report unfavorable health in the last six years of life declined two months from 1987-2008. To the author's knowledge, this is the first study to examine trends in SRH at the end of life. I also find no change in the length of time spent with at least one end-of-life IADL or ADL limitation from 1997-2008, barring a slight increase in the most recent period.

These findings are generally consistent with prior work that documents an unchanging prevalence of ADL limitations from 1995-2009 in the last 2 years of life. While others use repeated cross sections of the Medicare Current Beneficiaries Survey linked to death records from 1991-2009 to document a decline in the prevalence of ADL and IADL limitations in the last 5 years of life in the 1990's, they find no significant change in the following decade (the main focus of this analysis). However, my findings are in contrast to those by that consider six major chronic conditions and find that the adult disease burden may have grown over a similar period. Perhaps our findings differ because of the operationalization of disability versus chronic conditions. A growing disease burden might not translate to a higher prevalence of reporting one or more limitation, especially if the increases in chronic conditions are among people who already have at least one disability.

UNITY Biotechnology, a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced 12-week and 18-week data from its Phase 2 BEHOLD study of UBX1325, a senolytic Bcl-xL inhibitor, in patients with diabetic macular edema (DME).

At 18 weeks after a single UBX1325 injection, the mean change in best corrected visual acuity (BCVA) of UBX1325-treated subjects was an increase of 6.1 ETDRS letters, representing an improvement of +5.0 ETDRS letters compared to sham-treated subjects. In addition, patients treated with UBX1325 maintained central subfield thickness (CST) compared to sham-treated patients who demonstrated progressive worsening of CST (i.e., increased retinal thickness) through 18 weeks. The separation of UBX1325-treated patients from sham-treated patients at 18 weeks in measures of both visual function and retinal structure following a single UBX1325 injection suggests that one dose could have a durable therapeutic effect. The current standard of care for DME with the leading anti-VEGF therapeutic requires 3-5 monthly loading doses followed by every 8-week dosing, imposing a significant treatment burden on patients.

"The 12- and 18-week results are especially impressive considering that UBX1325 was given as a single injection in a patient population in which anti-VEGF treatment was no longer providing optimal benefit. The vision gains observed are greater than what has been previously reported with the standard of care in similar patient populations, and the durability of effect suggests that UBX1325 could address the large unmet need for longer-lasting, disease-modifying treatments for patients with DME. These data represent an important and exciting step in validating the senolytic therapeutic concept that is core to UNITY's platform."

With the increase of age, the function and interaction of three unique intervertebral disc (IVD) compartments: the central nucleus pulposus (NP), the circumferential annulus fibrosus (AF), and the cranial and caudal cartilaginous endplates (CEP) continue to deteriorate, which is difficult to avoid. Normal IVD is the largest avascular structure in human body and exchanges metabolites via diffusion from the adjacent capillary bed penetrating the subchondral bone of the endplate and the capillaries around the fibrous ring. The main nutrient supply of the IVD comes from the bony endplate vasculature, and material exchange between the vertebral body and the IVD is carried out through the diffusion of the cartilaginous endplate, which is the nutrient supply route of the disc cells.

As life span increases, so does the cartilaginous endplate osteosclerosis changes, accompany with the number of microvessels under the bony endplate gradually decreases, and the permeability disappears, resulting in the imbalance of energy metabolism of nucleus pulposus cells. Consequently, microvessels under the bony endplate and nutrient availability at the bone-disc interface decreases may be a key factor of intervertebral disc degeneration (IDD) that could not be neglected.

During IVD degenerative process, there are inevitable interactions between the human IVD cells and adjacent non-IVD cells, including endothelial cells (ECs) which play a major part in vascular structure formation. The senescent vascular endothelial cellular accumulation, which leads to the altered cellularity, vascular regression, and extracellular matrix composition, might set the IVD on a slow course toward degeneration. Additionally, there is a positive association of the vascular endothelial cellular senescence with the decrease of microvasculature in the marrow space of the bony endplate, which can hinder transport from nutrient supply to the disc or result in changes in cell phenotype, even death.

In this study, the relationships between endothelial cellular senescence in the marrow space of the bony endplate and IVD degeneration were investigated using the aged mice model. Preliminary results showed that senolytics can alleviate endothelial cellular senescence in the marrow space of the bony endplate as evidenced by reduced senescence-associated secretory phenotype. In the aged mice model, we found decreased height of IVD accompanied by vertebral bone mass loss and obvious changes to the endplate subchondral vasculature, which may lead to the decrease in nutrition transport into IVD. These findings may provide evidence that senolytics can eliminate the senescent cells and facilitate microvascular formation in the marrow space of the bony endplate. Targeting senescent cellular clearance mechanism to increase nutrient supply to the avascular disc suggests a potential treatment value of senolytics for IVD degenerative diseases.

Immune response plays an important role in stroke. As soon as a blood clot wedges itself in a blood vessel, the brain sends an "SOS" signal to activate the immune system. This rapid immune response aims to clear out the cell debris, limit brain damage, and kick-start brain repair processes. However, the function of the immune system is diverse and complex, and different types of immune cells may play distinct beneficial or detrimental roles in a damaged brain.

This study identified a novel subset of CD8+ regulatory-like T cells, or CD8+TRLs, as "first responders" to stroke. Attracted to the site of ischemic injury by a unique "homing" signal released by dying brain cells, CD8+TRLs reach the brain within 24 hours after stroke onset, where they release molecules that provide direct neuroprotective effects, as well as limit inflammation and secondary brain damage. "Creating shelf-stable and ready-to-use CD8+TRLs or developing a cocktail of neuroprotective signaling molecules released by those cells once they reach the brain could present effective future therapies against stroke and offer hope to hundreds of thousands of patients who are ineligible for treatments available to them currently."

CD8+TRLs enter the brain much faster than any other regulatory immune cells. Within 24 hours after researchers depleted these special CD8+TRLs from the bloodstream of stroke mice, the size of the brain region affected by ischemia expanded by 50% compared to animals whose CD8+TRL levels remained intact. Even more reassuringly, mice who received a transfusion of purified CD8+TRLs prepared in the lab fared better and recovered faster than those who were untreated for over five weeks. These unique CD8+TRLs, therefore, serve as early responders to rally defenses after stroke and may collaborate with other immune cells to safeguard the brain for a long time.

In 2013, Nir Barzilai and two other researchers got a grant from the National Institute on Aging to develop a roadmap to conduct, for the first time in history, a clinical trial that targets aging. They planned to test metformin, a drug that had been approved in the '90s for treating diabetes, and that was shown in epidemiological studies to prevent against conditions like heart attacks, cancer, and Alzheimer's. It also turned out to be very safe, with few, generally mild side effects. And it's dirt cheap: just six cents per dose.

The biggest obstacle they had was the Food and Drug Administration. The federal regulator adheres to a "one disease, one drug" model of approval. And because the agency does not recognize aging as a disease, there's no path forward for a drug to treat it. And even if there was, it's impractical to do a lifespan study - it would take decades and be astronomically expensive. The solution then would be to use biomarkers as a proxy, as researchers have with other treatments. Barzilai's plan was to launch a new kind of gold-standard trial, designed to prove that the onset of multiple chronic diseases, or comorbidities, associated with aging can be delayed by a single drug: metformin. The ambitious effort aimed to track 3,000 elderly people over five years to see if the medicine could hold off cardiovascular disease, cancer, and cognitive decline, along with mortality.

In 2015, he and a group of academics from more than a dozen top-tier universities met with the FDA to get its blessing for their Targeted Aging with Metformin, or TAME, trial. And to many people's surprise, the agency agreed. All that was left was funding it. Because metformin is a generic drug from which no one could make any money, the trial's sponsor wouldn't be a pharmaceutical company, but AFAR. A trial of the scale researchers were proposing would cost between 30 million and 50 million. The National Institutes of Health offered up just a small portion, about 9 million, toward the difficult but important task of screening for the best biomarkers for assessing if the aging process is actually being slowed. The rest of the money, Barzilai was convinced, could be raised from philanthropists. But despite interest from several people - at one point, Barzilai said, the Israeli American businessman Adam Neumann offered to pay for it all, before his WeWork empire evaporated - the required funds never materialized. "Those big billionaires, they want moonshots, they want a scientific achievement that will make people say 'wow'. TAME is not a moonshot. It's not even about scientific achievement really, it's more about political achievement. Metformin is a tool to get aging as an indication."

A new national poll of registered voters in the United States demonstrates broad bipartisan support for advancing research into longevity treatments that would extend healthy human lifespan. The poll, which was conducted by Public Policy Polling on behalf of The Alliance for Longevity Initiatives (A4LI), found that 70% of respondents support medical research that seeks to treat the cellular aging process as a means to prevent or delay the onset of all age-related chronic diseases. The majority of poll participants also believe that the US government should prioritize funding for this area of research.

However, Americans' support for aging research is in stark contrast to the realities of US biomedical research priorities. Currently, the National Institute of Aging's (NIA) Division of Aging Biology receives just 0.6% of the National Institutes of Health's (NIH) nearly 52 billion budget. Instead, most of the funding goes to specific diseases, such as Alzheimer's and cancer, despite longevity treatments having the potential to combat all age-related conditions at once.

Age-related chronic diseases and conditions have both enormous human and economic costs. Aging is the greatest risk factor for chronic ailments and death. Eighty percent of Americans 65 or older, have at least one chronic condition and 50 percent have at least two. Age-related chronic conditions are also America's most expensive diseases. Approximately 84 percent of all healthcare costs in the US are treatments for chronic diseases. The share of these costs is even higher for patients who receive healthcare through public programs. Ninety-nine percent of Medicare costs and 80 percent of Medicaid expenditures go toward the treatment of chronic diseases. As of 2016, direct healthcare treatment for chronic diseases costs 1.1 trillion in the US. This is nearly equivalent to six percent of America's gross domestic product (GDP).

While the cost of age-related chronic conditions is tremendous, the economic benefits of effectively treating aging are even more significant. It is estimated that increasing healthy life expectancy by just one year would be worth 38 trillion in economic returns in the US and by 10 years these savings and additional economic output would accumulate to 367 trillion.

Numerous studies have been attempted to link Alzheimer's disease (AD)-related molecules to the pathogenesis of AD: APOE ε4-associated mechanisms such as amyloid-β (Aβ) clearance and aggregation, cerebral energy metabolism, neuroinflammation, neurovascular function, and synaptic plasticity, and presenilin-related ones such as Aβ production, calcium homeostasis, and neurogenesis. Such heterogeneous and multiple mechanistic pathways may work cumulatively over a lifetime to increase an individual's risk of AD. Nonetheless, the pathogenesis hypothesis needs to make logical connections with several confirmed findings, that is, the existence of both amyloid plaques (APs) and neurofibrillary tangles (NFTs), anatomical characteristics of neurodegeneration. The amyloid hypothesis has long been at the center of discussions. Aβ is believed to be toxic to neurons and have various mechanisms of action.

As an alternative to the Aβ hypothesis, in this paper, I propose that excessive (or aberrant) and maladaptive synaptic plasticity is the cause of AD. Previously, plasticity failure was proposed as a cause of AD. In that hypothesis, AD results if the demand for plastic remodeling exceeds the biological capacity to fulfill it: Familial Alzheimer's disease (FAD)-causing mutations of APP increase the demand for plastic remodeling by shifting the balance of its processing toward more toxic form of Aβ. Another example is the malignant synaptic growth hypothesis, which suggests that AD develops if the positive feedback mechanism during synaptic modification is dysregulated. The authors suggest that Aβ prevents neurons from malignant synaptic growth by impairing the function of plasticity-related synaptic molecules and that FAD-linked mutations produce types of Aβ which have a weaker neuroprotective effect against it. Further, network abnormalities have also been discussed as potential mechanisms of cognitive dysfunction in AD. In these papers, Aβ is considered to be a central molecule causing network abnormalities.

In contrast to the previous discussions, the hypothesis proposed here states that excessive/aberrant synaptic plasticity is a root cause for cognitive dysfunction in AD and that cognitive dysfunction is developed through maladaptive neuronal connections, hyperexcitability of neuronal network and abnormal process of synaptic remodeling. APP is a key player in synaptic plasticity, and in FAD, the mutant APP or presenilin leads to aberrant plasticity through altered APP metabolism and function, which initially manifest as neuronal network abnormalities.

Decades of research do not necessarily support only the amyloid hypothesis, but also can be utilized to hypothesize excessive/aberrant and maladaptive synaptic plasticity as the cause of AD. If this hypothesis is correct, an important goal aimed at delaying the onset of AD and slowing or halting the disease progression is to find ways to adaptively regulate synaptic remodeling without interfering with necessary changes. This requires an understanding of the fundamental mechanism of synapse dynamics, and the characteristics of the stage of synaptic plasticity (formation, maturation, or elimination) at which a person developing AD is affected. Because of heterogeneity between individuals, identifying the stage of synaptic plasticity at which individuals are prone to error is a prerequisite for providing each person the appropriate intervention.

The majority of people would like to live to the age of 120 years or more if their health remained good and nearly one half would like an unlimited lifespan. About one-third of people would be prepared to take life extension or anti-ageing therapies now. The possibility that a pill might prevent ageing and increase lifespan is tantalising for most people. As a result, anti-ageing and life extension therapies are often the focus for media hype despite the absence of definitive human data.

In this review, the term 'gerotherapeutics' is used to refer to drugs that target ageing biology, and that have been developed using similar approaches to those used to develop drugs for diseases. A major scientific endeavour is underway to find biological switches that can manipulate ageing. This research aims to discover new gerotherapeutic drugs that both reduce the burden of ageing-related diseases, and extend lifespan. There are many ageing-related diseases where the incidence increases exponentially throughout old age, including Alzheimer's disease, some cancers, ischaemic heart disease, ischemic stroke, and chronic obstructive pulmonary disease. The biological changes of ageing are a major risk factor these diseases. The hope is that gerotherapeutic drugs might reduce the impact of these ageing-related diseases with a single therapy.

Over the last two decades there has been a marked increase in the number of interventions reported to increase lifespan, and delay ageing and disease, in laboratory animals. However, the development of gerotherapeutic drugs is still in its infancy, and no gerotherapeutic drug has yet been shown to increase human lifespan or been licenced for an indication related to ageing. 'Anti-ageing' is a term mostly used to promote products that are not regulated or licenced. There are many drugs, supplements and other treatments that are marketed as anti-ageing and can be accessed direct-to-consumer from pharmacies or online. None of these treatments can support their anti-ageing claims with high quality clinical trials equivalent to those that are required for the registration of drugs for the treatment of individual diseases.

There is very little information about how many people are taking anti-ageing therapies and gerotherapeutic drugs or what they are taking. It is likely that most doctors, including geriatricians, will have some or many patients using these treatments without supervision, so will need to have some knowledge about them. This review focuses on gerotherapeutics that have an established basic scientific foundation and/or where there is the possibility of widespread use in the community. It also provides a summary of how these drugs are being discovered, using traditional drug discovery approaches, repurposing, or by investigating populations with exceptional longevity.

Neurodegenerative diseases (NDs) are fatal chronic diseases of the central nervous system (CNS), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and transmissible spongiform encephalopathies (TSEs). A hallmark of NDs is the intracellular or extracellular deposition of cellular proteins into ordered high-molecular weight fibrils, termed amyloid. Amyloid fibrils then act as seeds that bind and convert proteins of the same kind into their abnormal isoforms (seeding). Protein aggregation occurs sequentially in anatomically connected areas, suggesting a progressive spreading throughout the CNS of affected individuals. Approximately 90% of NDs occur sporadically, and only few cases are linked to mutations in aggregation-prone proteins or proteins involved in their processing or trafficking. The etiology of idiopathic NDs remains unknown.

NDs are multifactorial diseases, triggered by enhanced age as well as genetic and environmental risk factors. Pathogens, and especially viruses, are suspected to act as etiological factors in several NDs. An impressive number of studies highlights that viruses, through their capacity to hijack the host cell machinery and induce inflammation, trigger and/or contribute to degenerative processes. Viral infections can activate astrocytes and microglia or induce CNS infiltration by peripheral immune cells, thereby causing neuroinflammation. Some viruses can enter the CNS and affect neurodegeneration via lytic egress from infected neurons by impairing neuronal processes or by inducing neuronal apoptosis. In this review, we discuss how viruses can also directly contribute to disease-associated protein misfolding and subsequent processes of protein aggregate spreading.

Both clinical and preclinical research suggest that osteoarthritis (OA)-related pain is induced by increased nociceptive input from the joint through alterations in pain signaling pathways in the central and peripheral nervous system. For example, activation of nociceptive neurons in the dorsal root ganglion (DRG) through nerve growth factor (NGF) to activate nociceptive neurons by binding tropomyosin receptor kinase A (TrkA), chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor (TNF), and Netrin-1 correlates with OA-related pain. Moreover, these axon guidance proteins induce nociceptive neuron projection locally in multiple joint tissues, including synovium and subchondral bone, leading to an exaggerated pain response.

Currently, it is unknown whether senolytic drugs affect the degree of innervation of sensory nerve fibers in the synovium and subchondral bone and if there are subsequent changes to nociceptive signaling pathways, like CGRP and NGF/TrkA, to alleviate OA-related joint pain. Here, we investigated the therapeutic potential of senolytics against a spontaneously developed OA. Using 21 and 22- month-old mice, we analyzed the effects of two senolytic drugs (ABT263 and the combination of dasatinib and quercetin) on structural alterations (including articular cartilage and subchondral bone degeneration and synovitis) and pain in knee joints. We further analyzed pain-related sensory innervation and axonal growth-promoting factors that stimulate neuronal sprouting in the joints and DRG and knee joint angiogenesis to address putative nociceptive mechanisms by which senolytic treatment reduces OA pain.

Selective elimination of the senescent cells that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. We suggest that systemic administration of ABT263 and the dasatinib and quercetin combination is an exciting therapeutic approach to age-related OA pain.

Comparative analyses of bats indicate that hibernation is associated with increased longevity among species. However, it is not yet known if hibernation affects biological ageing of individuals. Here, we use DNA methylation (DNAm) as an epigenetic biomarker of ageing to determine the effect of hibernation on the big brown bat, Eptesicus fuscus. First, we compare epigenetic age, as predicted by a multi-species epigenetic clock, between hibernating and non-hibernating animals and find that hibernation is associated with epigenetic age. Second, we identify genomic sites that exhibit hibernation-associated change in DNAm, independent of age, by comparing samples taken from the same individual in hibernating and active seasons.

This paired comparison identified over 3000 differentially methylated positions (DMPs) in the genome. Genome-wide association comparisons to tissue-specific functional elements reveals that DMPs with elevated DNAm during winter occur at sites enriched for quiescent chromatin states, whereas DMPs with reduced DNAm during winter occur at sites enriched for transcription enhancers. Furthermore, genes nearest DMPs are involved in regulation of metabolic processes and innate immunity. Finally, significant overlap exists between genes nearest hibernation DMPs and genes nearest previously identified longevity DMPs. Taken together, these results are consistent with hibernation influencing ageing and longevity in bats.

In conclusion, application of a multi-species bat epigenetic clock provides strong evidence that hibernation is associated with slower epigenetic ageing. The multi-species clock explains 94% of the variation in the chronological ages of both hibernating and non-hibernating big brown bats; however, the clock estimates are equal to or greater than the chronological age, suggesting big brown bats age slightly faster than a 'typical' bat, especially during the active period.