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Cellular senescence is characterized by an irreversible cell cycle arrest and a pro‐inflammatory senescence‐associated secretory phenotype (SASP), which is a major contributor to aging and age‐related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single‐nuclei and single‐cell RNA‐seq in the hippocampus from young and aged mice. We observed an age‐dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK‐ATTAC mice, in which p16Ink4a‐positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof‐of‐concept for senolytic interventions' being a potential therapeutic avenue for alleviating age‐associated cognitive impairment. Senescence is a major contributor to aging and age‐related diseases. However, it is still unknown whether senolytics impact on cognitive function during the aging process. We found that both pharmacogenetic clearance of p16Ink4a senescent cells or treatment with senolytic cocktail Dasatinib and Quercetin, reduced senescent microglia in the hippocampus and improved cognitive function in aged mice.

Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially. Autophagy declines with age, yet it is unclear if restoration of autophagy extends lifespan. Here, the authors demonstrate in murine models that the inhibition of Atg5 induces ageing phenotypes and reduces lifespan, whilst autophagy restoration partially reverses these phenotypes with accelerated tumorigenesis.

Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sublethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations, metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial reactive oxygen species production via NADPH oxidase 4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions. Cancer treatments save lives, but they can also be associated with long-term side effects which greatly reduce quality of life; former patients often face fatigue, memory loss, frailty, higher likelihood of developing other cancers, and overall accelerated aging. Senescence is a change in a cell’s state that follows damage and is associated with aging. When a cell becomes senescent it stops dividing, can promote inflammation and may damage other cells. Research has shown that cancer treatment increases the numbers of cells entering senescence, potentially explaining the associated long-term side effects. A new class of drugs known as senolytics can kill senescent cells, but whether they could help to counteract the damaging effects of cancer treatments remain unclear. To explore this question, Fielder et al. focused on mice having received radiation therapy, which also exhibit the long-term health defects observed in human patients. In these animals, a single, short senolytic treatment after irradiation nearly erased premature aging; frailty did not increase faster than normal, new cancers were less prevalent, and the rodents retained good memory and muscle function for at least one year after irradiation. Even mice treated later in life, after frailty was already established, showed some improvement. In addition, multiple tissues, including the brain and the liver, hosted fewer senescent cells in the animals treated with senolytics, even up to old age. Research should now explore whether these remarkable effects could also be true for humans.

Chronic inflammation is a common feature of many age‐related conditions including neurodegenerative diseases such as Alzheimer's disease. Cellular senescence is a state of irreversible cell‐cycle arrest, thought to contribute to neurodegenerative diseases partially via induction of a chronic pro‐inflammatory phenotype. In this study, we used a mouse model of genetically enhanced NF‐κB activity (nfκb1−/−), characterized by low‐grade chronic inflammation and premature aging, to investigate the impact of inflammaging on cognitive decline. We found that during aging, nfkb1−/− mice show an early onset of memory loss, combined with enhanced neuroinflammation and increased frequency of senescent cells in the hippocampus and cerebellum. Electrophysiological measurements in the hippocampus of nfkb1−/− mice in vitro revealed deficits in gamma frequency oscillations, which could explain the decline in memory capacity. Importantly, treatment with the nonsteroidal anti‐inflammatory drug (NASID) ibuprofen reduced neuroinflammation and senescent cell burden resulting in significant improvements in cognitive function and gamma frequency oscillations. These data support the hypothesis that chronic inflammation is a causal factor in the cognitive decline observed during aging. Chronic inflammation induces cellular senescence and leads to premature aging and cognitive decline. Anti‐inflammatory treatment reduces neuroinflammation and senescent cell burden, and ameliorates cognitive impairment.

Increased activation of the major pro‐inflammatory NF‐κB pathway leads to numerous age‐related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF‐κB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF‐κB signalling, such as that which occurs in several age‐related chronic diseases. In this study, we investigated whether rapamycin could ameliorate age‐associated phenotypes in a mouse model of genetically enhanced NF‐κB activity (nfκb1−/−) characterized by low‐grade chronic inflammation, accelerated aging and CLD. We found that, despite showing no beneficial effects in lifespan and inflammaging, rapamycin reduced frailty and improved long‐term memory, neuromuscular coordination and tissue architecture. Importantly, markers of cellular senescence, a known driver of age‐related pathology, were alleviated in rapamycin‐fed animals. Our results indicate that, in conditions of genetically enhanced NF‐κB, rapamycin delays aging phenotypes and improves healthspan uncoupled from its role as a suppressor of inflammation.

Although ageing can be understood in terms of associated hallmarks and biomarkers, the processes which connect and cause these phenotypes are ill-defined. Here we suggest a unifying model of ageing as four distinct processes which connect the major observations and evidence into a single framework. It explains, from a single initial cause to the ultimate outcomes and diseases, why we age and die. We suggest that although DNA damage is crucial to shift homeostasis, ageing itself is not caused by simple DNA damage accumulation. Instead, only specific sites of damage are relevant when they affect selection and the resulting ageing processes. For clarity, each process is given a name. The first process, celerisis, results from the natural course of tissue-level selection for cells with elevated metabolic and proliferative rate. If the damaged DNA site gives the cell a selective advantage, it can spread within the tissue causing hyperfunctional diseases including cancer and fibrosis. However, many ageing phenotypes are more associated with hypofunction. Therefore, we suggest that our tissues have a mechanism to prevent the spread of hyperfunctional cells. In proliferative tissues, a second process, intrinsic ageing, is the result of this defence mechanism induced through cell communication via Notch. Slower metabolising mutants induce epigenetic changes in faster cells, and then epigenetically slowed cells slow other cells, causing gradual metabolic slowdown across tissues. The third process, extrinsic ageing, could then result directly from metabolic slowdown as body cells use less ATP. Mitochondria reduce catabolism, restoring ATP levels by burning less glucose and lipid. Build-up of these fuels in the cytoplasm reduces import, restoring equilibrium but inducing insulin resistance (IR), while the excess fuel is diverted to the adipose, causing weight gain, chronic inflammation, and metabolic syndrome. These outcomes could then combine with intrinsic ageing to induce age-related disease. The final process of mitochondrial selection induces intrinsic ageing of single celled life as well as post-mitotic tissues and organisms. Together, the four processes produce a detailed mechanistic map that explains the evolutionary significance of ageing, removing old paradoxes, and connecting the hallmarks into a causal framework that furthers our understanding.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://fairdomhub.org/models/851?version=1Funder Information DeclaredNovo Nordisk Fonden Challenge Programme: Harnessing the Power of Big Data to Address the Societal Challenge of Aging, NNF17OC0027812NIHR Newcastle Biomedical Research Centre, https://ror.org/044m9mw93

Single-ingredient dietary supplements have demonstrated some potential to extend lifespan and improve healthspan; however, the efficacy of defined multi-ingredient nutraceuticals remains underexplored. Senolytic interventions have been successful in reducing multi-morbidity, frailty, and cognitive decline in animal models and are seen as promising anti-ageing interventions in mammals. We compared the effects of a 12-ingredient nutraceutical on mice lifespan and healthspan markers with that of a high efficacy senolytic intervention consisting of a low dose of Navitoclax combined with the specific mitochondrial uncoupler BAM15. Both interventions were started at old age (20 months). The supplement was given daily until the end of the experiment (30 months of age), but the senolytic intervention consisted of two short (5 days each) rounds of treatment at 20 and 23 months of age. Despite late onset, both interventions increased median lifespan similarly by around 20% over controls. The senolytic intervention significantly reduced frailty progression and improved cognitive function after the second round of treatment, but without subsequent treatment, these effects appeared to wane at later ages. The multi-ingredient supplement tended to reduce frailty progression steadily with time, albeit not significant, and maintained cognitive function. Mechanistically, in vitro, there was no evidence of senolytic activity of the multi-ingredient nutraceutical as a whole nor of its individual ingredients. Continuous multi-ingredient dietary supplementation shows promise in achieving comparable anti-ageing efficacy as a senolytic intervention.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Discussion section: -The numbers were corrected: \"However, control lifespans in the present study (703 days) were shorter than in our previous study on the same mouse strain (median lifespan of 810 days).\" -The below paragraph was updated as: \"If those deaths were censored, the resulting median lifespan in the controls equalled 719 days, the DS group equalled 860.5 days, and SEN group equalled 852 days (Supplementary Fig. S4). Following censoring, the median lifespans of the DS and the SEN group were 19.7% and 18.5% longer than the controls respectively. This suggests that in relative terms our results are robust to this confounding factor.\" Figure 2 legend: Mixed up in orders were corrected as follows. \"Health span effects. A) Comparison between frailty indices in present (blue) and previous [28] (black) controls. All animals were male C57Bl/6J mice. Individual frailty indices (dots), regression lines (solid lines) and 95% confidence intervals (dotted lines) are shown. Frailty indices in the DS (B) and SEN (C) group in comparison to controls. Frailty indices for each animal (dots) and linear regression lines from baseline to every assessment time point are indicated to illustrate the kinetic developments. p values for the differences in regression slopes to that of control are shown. D) Spontaneous alternation in a Y-maze 1 month following the first and second round of senolytic treatment as percentage change from each mouses pre-treatment performance. Percentage changes of individual mice are illustrated as dots. Data are mean plus-minus SD, n≥3. ANOVA p values for differences between controls and treatment groups are indicated.\"

Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that targets the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.

Anti-senescence interventions are exceptionally effective in alleviating a wide range of age-associated diseases and disabilities. However, the sensitivity and specificity of current senolytic interventions are limited. Mitochondrial dysfunction is an integral part of the senescent phenotype and we demonstrate that specific loss of complex I-linked coupled respiration and the inability to maintain mitochondrial membrane potential upon respiratory stimulation are early and persistent features in a cell’s progression towards senescence. We thus identify senescence-associated mitochondrial dysfunction as a targetable vulnerability of senescent cells and show that further decreasing mitochondrial membrane potential of senescent cells with a low concentration of a mitochondrial uncoupler synergistically enhances the in vitro senolytic efficacy of BH3 mimetic drugs, including Navitoclax, by up two orders of magnitude. Moreover, in an in vivo mouse model of radiation-induced premature ageing, we show that a short-term intervention combining the mitochondrial uncoupler BAM15 with Navitoclax at a dose two orders of magnitude lower than typically used reduces frailty and improves cognitive function for at least 8 months after irradiation. Therefore our study shows that compromised mitochondrial functional capacity is a specific vulnerability of senescent cells which can be targeted by mild uncoupling in vitro and in vivo.