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Background Chronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer’s disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Methods Post-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed. Results We found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.

Supplementary Figures S1 - S10, Tables S1 - S2

Alpha-ketoglutarate (AKG) is an intermediate in the Krebs cycle involved in various metabolic and cellular pathways. As an antioxidant, AKG interferes in nitrogen and ammonia balance, and affects epigenetic and immune regulation. These pleiotropic functions of AKG suggest it may also extend human healthspan. Recent studies in worms and mice support this concept. A few studies published in the 1980s and 1990s in humans suggested the potential benefits of AKG in muscle growth, wound healing, and in promoting faster recovery after surgery. So far there are no recently published studies demonstrating the role of AKG in treating aging and age-related diseases; hence, further clinical studies are required to better understand the role of AKG in humans. This review will discuss the regulatory role of AKG in aging, as well as its potential therapeutic use in humans to treat age-related diseases.

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons.To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice.In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data shows that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Almost since the discovery that mutations in the LMNA gene, encoding the nuclear structure components lamin A and C, lead to Hutchinson-Gilford progeria syndrome, people have speculated that lamins may have a role in normal aging. The most common HPGS mutation creates a splice variant of lamin A, progerin, which promotes accelerated aging pathology. While some evidence exists that progerin accumulates with normal aging, an increasing body of work indicates that prelamin A, a precursor of lamin A prior to C-terminal proteolytic processing, accumulates with age and may be a driver of normal aging. Prelamin A shares properties with progerin and is also linked to a rare progeroid disease, restrictive dermopathy. Here, we describe mechanisms underlying changes in prelamin A with aging and lay out the case that this unprocessed protein impacts normative aging. This is important since intervention strategies can be developed to modify this pathway as a means to extend healthspan and lifespan.

The budding yeast Saccharomyces cerevisiae (S. cerevisiae) has relatively short lifespan and is genetically tractable, making it a widely used model organism in aging research. Here, we carried out a systematic and quantitative investigation of yeast aging with single-cell resolution through transcriptomic sequencing. We optimized a single-cell RNA sequencing (scRNA-seq) protocol to quantitatively study the whole transcriptome profiles of single yeast cells at different ages, finding increased cell-to-cell transcriptional variability during aging. The single-cell transcriptome analysis also highlighted key biological processes or cellular components, including oxidation-reduction process, oxidative stress response (OSR), translation, ribosome biogenesis and mitochondrion that underlie aging in yeast. We uncovered a molecular marker of FIT3, indicating the early heterogeneity during aging in yeast. We also analyzed the regulation of transcription factors and further characterized the distinctive temporal regulation of the OSR by YAP1 and proteasome activity by RPN4 during aging in yeast. Overall, our data profoundly reveal early heterogeneity during aging in yeast and shed light on the aging dynamics at the single cell level.

Despite accumulating evidence that supports the beneficial effects of physical exercise in inhibiting cancer progression, whether exercise modulates its effects through systemic and cellular changes in iron metabolism and immune-tumor crosstalk is unknown. Cancer cells have greater metabolic requirements than normal cells, with their survival and proliferation depending largely on iron bioavailability. Although iron is an essential mineral for mitogenesis, it also participates in a form of iron-dependent programmed cell death termed ferroptosis. In this short hypothesis paper, we speculate that modulating iron bioavailability, transport and metabolism with regular exercise can have significant implications for tumor and stromal cells in the tumor microenvironment, by affecting multiple tumor-autonomous and stromal cell responses.

Introduction Despite associated with multiple geriatric disorders, whether housing type, an indicator of socioeconomic status (SES) and environmental factors, is associated with accelerated biological aging is unknown. Furthermore, although individuals with low-SES have higher body mass index (BMI) and are more likely to smoke, whether BMI and smoking status moderate the association between SES and biological aging is unclear. We examined these questions in urbanized low-SES older community-dwelling adults. Methods First, we analyzed complete blood count data using the cox proportional hazards model and derived measures for biological age (BA) and biological age acceleration (BAA, the higher the more accelerated aging) (N = 376). Subsequently, BAA was regressed on housing type, controlling for covariates, including four other SES indicators. Interaction terms between housing type and BMI/smoking status were separately added to examine their moderating effects. Total sample and sex-stratified analyses were performed. Results There were significant differences between men and women in housing type and BAA. Compared to residents in ≥3 room public or private housing, older adults resided in 1-2 room public housing had a higher BAA. Furthermore, BMI attenuated the association between housing type and BAA. In sex-stratified analyses, the main and interaction effects were only significant in women. In men, smoking status instead aggravated the association between housing type and BAA. Conclusion Controlling for other SES indicators, housing type is an independent socio-environmental determinant of BA and BAA in a low-SES urbanized population. There were also sex differences in the moderating effects of health behaviors on biological aging.

Background Alzheimer's disease (AD) is a chronic condition that progresses over time. While several therapeutic approaches have been developed, none have substantially altered disease progression. One explanation is that the disease is multi factorial. Objective Using the Affirmativ Health Personal Therapeutic Program (PTPr), we sought to determine whether a comprehensive and personalized program could improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early stage AD. Methods 35 individuals submitted blood samples and Montreal Cognitive Assessment (MoCA) scores, and answered intake questions. Individuals and caregivers participated in a four-day immersion program, which included Personal Therapeutic Plans (PTP), consultations with clinical practitioners, and explanations of the PTPr and PTP. Participants had follow-up by telemonitoring, with repeat blood sample analysis, updates regarding lifestyle choices, current medications and supplements, and MoCA testing at least once between 3 and 12 months after the PTPr. Results By comparing baseline to follow-up testing, we determined several risk factor scores, including blood glucose and insulin levels, and levels of vitamins B12, D3, and E, improved either in the entire participant pool or specifically in individuals with measures outside the normal range for specific factors. MoCA scores were stabilized in the entire participant pool and significantly improved in individuals scoring 24 or less at baseline. Conclusion Our findings provide evidence that a comprehensive and personalized approach designed to mitigate AD risk factors can improve risk factor scores and stabilize cognitive function, warranting more extensive and placebo-controlled clinical studies.

Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD(+) enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.

Diseases that affect the mitochondrial electron transport chain (ETC) often manifest as threshold effect disorders, meaning patients only become symptomatic once a certain level of ETC dysfunction is reached. Multiple processes work to control proximity to the critical ETC threshold and as a consequence there can be significant variability in disease presentation among patients. Identification of such control processes remains an ongoing goal. Checkpoint signaling comprises a collection of alert mechanisms activated in cells in response to nuclear DNA damage. Well-defined hierarchies of proteins are involved in both sensing and signaling DNA damage, with ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) acting as pivotal signaling kinases. In the nematode C. elegans, severe reduction of mitochondrial ETC activity shortens life, as in humans, but mild reduction extends life as a consequence of survival strategies that are invoked under these circumstances. Here we show that removal of ATL-1, the worm ortholog of ATR, unexpectedly lessens the severity of ETC dysfunction, but removal of ATM does not. Multiple genetic and biochemical tests show no evidence for increased mutation or DNA breakage in animals exposed to ETC disruption. Instead, we find that reduced ETC function alters nucleotide ratios within both the ribo- and deoxyribo-nucleotide pools, and causes stalling of RNA polymerase, which is also known to activate ATR. Unexpectedly, atl-1 mutants confronted with mitochondrial ETC disruption maintain normal levels of oxygen consumption and have an increased abundance of translating ribosomes. This suggests checkpoint signaling by ATL-1 normally dampens cytoplasmic translation. Taken together, our data suggests a model whereby ETC insufficiency in C. elegans results in nucleotide imbalances leading to stalling of RNA polymerase, activation of ATL-1, dampening of global translation and magnification of ETC dysfunction. Loss of ATL-1 effectively reverses the severity of ETC disruption so that animals become phenotypically closer to wild type.

While the detrimental effects of binge drinking are well recognized, low-to-moderate alcohol consumption may be beneficial to health, although the underlying mechanism(s) remains elusive. In this opinion article, we will examine the effects of low dose alcohol consumption from the perspective of epigenetic modulation. Biochemically, alcohol is metabolized into acetate and subsequently to acetyl-coA, which can modulate histone acetylation levels. While elevated levels of acetyl-CoA are detrimental for longevity, we argue that diminished acetyl-CoA also negatively affects fatty acid biosynthesis and histone acetylation, which plays a critical role in gene expression and, ultimately, healthspan. Since mitochondrial function and glucose metabolism, which provides the main source of nucleocytoplasmic acetyl-CoA, are compromised with age, alcohol-derived acetate could be an alternative source of acetyl-CoA to compensate. Hence, the health benefits of low ethanol consumption may be more pronounced after midlife, since mitochondrial function and/or glucose metabolism are diminished in this phase of the life course. Indeed, various clinical alcohol consumption studies concur with this notion, and have shown that a low dose of regular alcohol intake after midlife brings about various health and survival benefits. The requirement for regular alcohol intake may also reflect the transient nature of ethanol-induced histone acetylation. Conversely, ethanol may also stimulate carcinogenesis by inhibiting DNA methylation, as it was shown to reduce various pathways leading to DNA and histone methylation. However, unlike acetylation, where ethanol directly increases the substrate for acetylation, this effect was only observed in the high alcohol exposure cohort. While alcohol-derived acetate may be beneficial for health after midlife, various detrimental effects of alcohol consumption remain, and hence, we do not advocate excessive drinking to increase acetate. This opinion article establishes a possible role of ethanol-derived acetate in achieving homeostasis and sustaining an organism's healthspan.

We recently identified microRNAs (miRNAs) associated with chronic mucus hypersecretion (CMH) in chronic obstructive pulmonary disease (COPD), which were expressed in both airway epithelial cells and fibroblasts. We hypothesized that these miRNAs are involved in communication between fibroblasts and epithelium, contributing to airway remodeling and CMH in COPD. Primary bronchial epithelial cells (PBECs) differentiated at the air–liquid interface, and airway fibroblasts (PAFs) from severe COPD patients with CMH were cultured alone or together. RNA was isolated and miRNA expression assessed. miRNAs differentially expressed after co-culturing were studied functionally using overexpression with mimics in mucus-expressing human lung A549 epithelial cells or normal human lung fibroblasts. In PBECs, we observed higher miR-708-5pexpression upon co-culture with fibroblasts, and miR-708-5p expression decreased upon mucociliary differentiation. In PAFs, let-7a-5p, miR-31-5p and miR-146a-5p expression was significantly increased upon co-culture. miR-708-5p overexpression suppressed mucin 5AC (MUC5AC) secretion in A549, while let-7a-5poverexpression suppressed its target gene COL4A1 in lung fibroblasts. Our findings suggest that let-7a-5p, miR-31-5p and miR-146a-5p may be involved in CMH via fibroblasts–epithelium crosstalk, including extracellular matrix gene regulation, while airway epithelial expression of miR-708-5p may be involved directly, regulating mucin production. These findings shed light on miRNA-mediated mechanisms underlying CMH, an important symptom in COPD.

Complexity is a fundamental feature of biological systems. Omics techniques like lipidomics can simultaneously quantify many thousands of molecules, thereby directly capturing the underlying biological complexity. However, this approach transfers the original biological complexity to the resulting datasets, posing challenges in data reduction and analysis. Aging is a prime example of a process that exhibits complex behaviour across multiple scales of biological organisation. The aging process is characterised by slow, cumulative and detrimental changes that are driven by intrinsic biological stochasticity and mediated through non-linear interactions and feedback within and between these levels of organization (ranging from metabolites, macromolecules, organelles and cells to tissue and organs). Only collectively and over long timeframes do these changes manifest as the exponential increases in morbidity and mortality that define biological aging, making aging a problem more difficult to study than the aetiologies of specific diseases. But aging’s time dependence can also be exploited to extract key insights into its underlying biology. Here we explore this idea by using data on changes in lipid composition across the lifespan of an organism to construct and test a LipidClock to predict biological age in the nematode Caenorhabdits elegans. The LipidClock consist of a feature transformation via Principal Component Analysis followed by Elastic Net regression and yields and Mean Absolute Error of 1.45 days for wild type animals and 4.13 days when applied to mutant strains with lifespans that are substantially different from that of wild type. Gompertz aging rates predicted by the LipidClock can be used to simulate survival curves that are in agreement with those from lifespan experiments.

Intermittent fasting (IF) remains the most effective intervention to achieve robust anti-aging effects and attenuation of age-related diseases in various species. Epigenetic modifications mediate the biological effects of several environmental factors on gene expression; however, no information is available on the effects of IF on the epigenome. Here, we first found that IF for 3 months caused modulation of H3K9 trimethylation (H3K9me(3)) in the cerebellum, which in turn orchestrated a plethora of transcriptomic changes involved in robust metabolic switching processes commonly observed during IF. Second, a portion of both the epigenomic and transcriptomic modulations induced by IF was remarkably preserved for at least 3 months post-IF refeeding, indicating that memory of IF-induced epigenetic changes was maintained. Notably, though, we found that termination of IF resulted in a loss of H3K9me(3) regulation of the transcriptome. Collectively, our study characterizes the novel effects of IF on the epigenetic-transcriptomic axis, which controls myriad metabolic processes. The comprehensive analyses undertaken in this study reveal a molecular framework for understanding how IF impacts the metabolo-epigenetic axis of the brain and will serve as a valuable resource for future research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00537-z.

Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model organisms, clinical studies on potential geroprotectors are exceedingly rare, especially in healthy elders. This review aims to classify potential geroprotectors based on the mechanisms by which they influence aging. These pharmacological interventions can be classified into the following groups: those that prevent oxidation; proteostasis regulators; suppressors of genomic instability; epigenetic drugs; those that preserve mitochondrial function; inhibitors of aging-associated signaling pathways; hormetins; senolytics/senostatics; anti-inflammatory drugs; antifibrotic agents; neurotrophic factors; factors preventing the impairment of barrier function; immunomodulators; and prebiotics, metabiotics, and enterosorbents.

Increased healthcare and pharmaceutical understanding has led to the eradication of many childhood, infectious and preventable diseases; however, we are now experiencing the impact of aging disorders as the lifespan increases. These disorders have already become a major burden on society and threaten to become a defining challenge of our generation. Indications such as Alzheimer’s disease gain headlines and have focused the thinking of many towards dementia and cognitive decline in aging. Indications related to neurological function and related behaviors are thus an extremely important starting point in the consideration of therapeutics.However, the reality is that pathological aging covers a spectrum of significant neurological and peripheral indications. Development of therapeutics to treat aging and age-related disorders is therefore a huge need, but represents a largely unexplored path. Fundamental scientific questions need to be considered as we embark towards a goal of improving health in old age, including how we 1) define aging as a therapeutic target, 2) model aging preclinically and 3) effectively translate from preclinical models to man. Furthermore, the challenges associated with identifying novel therapeutics in a financial, regulatory and clinical sense need to be contemplated carefully to ensure we address the unmet need in our increasingly elderly population. The complexity of the challenge requires different perspectives, cross-functional partnerships and diverse concepts. We seek to raise issues to guide the field, considering the current state of thinking to aid in identifying roadblocks and important challenges early. The need for therapeutics that address aging and age-related disorders is acute, but the promise of effective treatments provides huge opportunities that, as a community, we all seek to enable effectively as soon as possible.

Establishing the pattern of abundance of molecules of interest during cell division has been a long-standing goal of cell cycle studies. In several systems, including the budding yeastSaccharomyces cerevisiae, cell cycle-dependent changes in the transcriptome are well studied. In contrast, few studies queried the proteome during cell division, and they are often plagued by low agreement with each other and with previous transcriptomic datasets. There is also little information about dynamic changes in the levels of metabolites and lipids in the cell cycle. Here, for the first time in any system, we present experiment-matched datasets of the levels of RNAs, proteins, metabolites, and lipids from un-arrested, growing, and synchronously dividing yeast cells. Overall, transcript and protein levels were correlated, but specific processes that appeared to change at the RNA level (e.g., ribosome biogenesis), did not do so at the protein level, and vice versa. We also found no significant changes in codon usage or the ribosome content during the cell cycle. We describe an unexpected mitotic peak in the abundance of ergosterol and thiamine biosynthesis enzymes. Although the levels of several metabolites changed in the cell cycle, by far the most significant changes were in the lipid repertoire, with phospholipids and triglycerides peaking strongly late in the cell cycle. Our findings provide an integrated view of the abundance of biomolecules in the eukaryotic cell cycle and point to a coordinate mitotic control of lipid metabolism.

An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.

Thanks to advances in modern medicine over the past century, the world’s population has experienced a marked increase in longevity. However, disparities exist that lead to groups with both shorter lifespan and significantly diminished health, especially in the aged. Unequal access to proper nutrition, healthcare services, and information to make informed health and nutrition decisions all contribute to these concerns. This in turn has hastened the ageing process in some and adversely affected others’ ability to age healthfully. Many in developing as well as developed societies are plagued with the dichotomy of simultaneous calorie excess and nutrient inadequacy. This has resulted in mental and physical deterioration, increased non-communicable disease rates, lost productivity and quality of life, and increased medical costs. While adequate nutrition is fundamental to good health, it remains unclear what impact various dietary interventions may have on improving healthspan and quality of life with age. With a rapidly ageing global population, there is an urgent need for innovative approaches to health promotion as individual’s age. Successful research, education, and interventions should include the development of both qualitative and quantitative biomarkers and other tools which can measure improvements in physiological integrity throughout life. Data-driven health policy shifts should be aimed at reducing the socio-economic inequalities that lead to premature ageing. A framework for progress has been proposed and published by the World Health Organization in its Global Strategy and Action Plan on Ageing and Health. This symposium focused on the impact of nutrition on this framework, stressing the need to better understand an individual’s balance of intrinsic capacity and functional abilities at various life stages, and the impact this balance has on their mental and physical health in the environments they inhabit. © 2019, The Author(s).

Lysosome function is compromised during aging and in many disease states. Interventions that promote lysosomal activity and acidification are thus of prime interest as treatments for longevity and health. Intracellular pH can be controlled by the exchange of protons for inorganic ions, and in cells from microbes to man, when potassium is restricted in the growth medium, the cytoplasm becomes acidified. Here we use a yeast model to show that potassium limited-cells exhibit hallmarks of increased acidity in the vacuole, the analog of the lysosome, and live long by a mechanism that requires the vacuolar machinery. The emerging picture is one in which potassium restriction shores up vacuolar acidity and function, conferring health benefits early in life and extending viability into old age. Against the backdrop of well-studied protein and carbohydrate restrictions that extend lifespan and healthspan, our work establishes a novel pro-longevity paradigm of inorganic nutrient limitation.

The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.