The accumulation of damage caused by oxidative stress has been linked to aging and to the etiology of numerous age-related diseases. The longevity gene, sirtuin 6 (SIRT6), promotes genome stability by facilitating DNA repair, especially under oxidative stress conditions. Here we uncover the mechanism by which SIRT6 is activated by oxidative stress to promote DNA double-strand break (DSB) repair. We show that the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to oxidative stress. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. Our results demonstrate a post-translational mechanism regulating SIRT6, and they provide the link between oxidative stress signaling and DNA repair pathways that may be critical for hormetic response and longevity assurance.

This cohort study evaluates whether socioeconomic factors, including sex, race and ethnicity, material deprivation, and rurality) are associated with the age at which patients are diagnosed with severe mental illness.

Background Non-Alcoholic Fatty Liver Disease (NAFLD), now referred to as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a widespread and complex health issue characterized by the accumulation of lipids in liver cells, not linked to alcohol consumption or other known liver problems. Despite its strong association with insulin resistance and obesity, a notable proportion of lean individuals develop NAFLD, suggesting the involvement of additional factors. Mitochondrial dysfunction has emerged as a potential contributor, given its role in lipid homeostasis and the generation of reactive oxidative species (ROS). Methods In this study, we took advantage of the mtDNA mutator mouse model, characterized by oxidative phosphorylation deficiency due to accelerated accumulation of mitochondrial DNA (mtDNA) mutations, to investigate how mitochondrial dysfunction affects liver homeostasis triggering fat accumulation. Results We found that mitochondrial dysfunction induces liver steatosis and inflammation in this mouse model at a young age, independent of obesity. Using quantitative mass spectrometry, we reveal that mitochondrial dysfunction alters the levels of multiple proteins involved in lipid metabolism, cholesterol homeostasis, and inflammation. In vitro data show a shift in cellular metabolism toward the glycolytic pathway and confirm the upregulation of inflammatory genes. These changes are associated with oxidative stress and occur independently of mtDNA molecule release into the cytoplasm. Conclusion Our findings demonstrate that liver steatosis might develop as result of mitochondrial dysfunction without obesity and insulin resistance, underscoring the importance of mitochondrial dysfunction in NAFLD development in lean individuals and providing valuable insights into the molecular mechanisms underlying this complex metabolic disorder. This mouse model offers a unique platform for further investigations aimed at unraveling the intricacies of NAFLD pathogenesis and potential therapeutic targets beyond conventional risk factors. ### Competing Interest Statement D.A.S is a consultant to, board member of, and owns equity in MetroBiotech (an EdenRoc company) and Life Bioscences, both working on longevity-based medicines. For list of all DAS activities see: . The other authors declare no conflict of interest in relation to this work. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. National Institutes of HealthNational Institutes of Health, https://ror.org/01cwqze88, R21OD037651, R00AG055683

On 1–2 November 2024, the annual Biomarkers of Aging conference welcomed academic and industry scientists, and partners from governmental and nongovernmental organizations, to Harvard Medical School in Boston, USA, to discuss new insights into measuring and monitoring human aging, with the aim of clinical translation. In this Meeting Report, we summarize the conference and offer potential future directions for the Biomarkers of Aging Consortium and the longevity science community at large.

Could lithocholic acid, a compound produced when gut bacteria process bile, be the missing link between a low-calorie diet and its age-defying effects? Experiments in mice, flies and nematode worms provide clues. Lithocholic acid might mediate calorie restriction’s health benefits.

Biological age refers to a person's overall health in aging, as distinct from their chronological age. Diverse measures of biological age, referred to as "clocks," have been developed in recent years and enable risk assessments and an estimation of the efficacy of longevity interventions in animals and humans. Although most clocks are trained to predict chronological age, clocks have been developed to predict more complex composite biological age outcomes, at least in humans. These composite outcomes can be made up of a combination of phenotypic data, chronological age, and disease or mortality risk. Here, we develop the first such composite biological age measure for mice: the mouse phenotypic age model (Mouse PhenoAge). This outcome is based on frailty measures, complete blood counts, and mortality risk in a longitudinally assessed cohort of male and female C57BL/6 mice. We then develop clocks to predict Mouse PhenoAge, based on multiomic models using metabolomic and DNA methylation data. Our models accurately predict Mouse PhenoAge, and residuals of the models are associated with remaining lifespan, even for mice of the same chronological age. These methods offer novel ways to accurately predict mortality in laboratory mice, thus reducing the need for lengthy and costly survival studies.

Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases. HIGHLIGHTS:OSK-GSTA4 provides a dynamic, Tet2-independent stress-resilience axis.Functional genomics pinpoints GSTA4 as a direct downstream effector activated by OSK.RPE aging involves progressive accumulation of 4-HNE that can be detoxified by GSTA4.Enhancing GSTA4 rejuvenates RPE cells, restores vision and is associated with lifespan-extending interventions.

Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response. Levels of the metabolic coenzyme NAD+ decline during aging, which is linked to many age-related diseases. Zhang et al. review recent clinical and translational evidence testing NAD+ supplementation in age-related diseases, highlighting therapeutic challenges and opportunities.

BACKGROUND:Polypharmacy, defined as the concurrent use of five or more medications, is common amongst older adults receiving home care services. The relationship between home care and polypharmacy may be critical to older people's health, but there is little research on this topic. OBJECTIVE:To understand the extent and type of evidence on individuals receiving home care services and experiencing polypharmacy. METHODS:This review followed the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. Three databases (MEDLINE, Embase, CINAHL) were systematically searched (December 2023) to identify studies with adult participants experiencing polypharmacy and receiving home care. RESULTS:Twenty-three studies were included. For individuals receiving home care services, the studies reported on the following: (i) prevalence of polypharmacy, (ii) interventions to reduce inappropriate polypharmacy, (iii) perceived role of home care workers, (iv) assessment of health literacy in individuals experiencing polypharmacy, and (v) factors associated with polypharmacy and potentially inappropriate medications (PIMs). Polypharmacy and PIMs were found to be associated with older age, female sex, increased frailty, living alone, poor economic situation and inaccuracies within medical records. Improved appropriateness of prescribing can be achieved through interprofessional interventions, efficient use of home care workers and improved health literacy. CONCLUSION:This review highlights research on the extent of polypharmacy in home care and ways to address it. Whilst there are suggestions for enhancing medication quality, key gaps remain in research into the experiences of care staff and recipients in managing medications and polypharmacy, which should be addressed.

BACKGROUND:Material disadvantage is associated with poor health, but commonly available area-based metrics provide a poor proxy for it. We investigate if a measure of material disadvantage could be constructed from UK primary care electronic health records. METHODS:Using data from Clinical Practice Research Datalink Aurum (May 2022) linked to the 2019 English Index of Multiple Deprivation (IMD), we sought to (1) identify codes that signified material disadvantage, (2) aggregate these codes into a binary measure of material disadvantage and (3) compare the proportion of people with this binary measure against IMD quintiles for validation purposes. RESULTS:We identified 491 codes related to benefits, employment, housing, income, environment, neglect, support services and transport. Participants with one or more of these codes were defined as being materially disadvantaged. Among 30,897,729 research-acceptable patients aged ≥18 with complete data, only 6.1% (n=1,894,225) were classified as disadvantaged using our binary measure, whereas 42.2% (n=13,038,085) belonged to the two most deprived IMD quintiles. CONCLUSION:Data in a major primary care research database do not currently contain a useful measure of individual-level material disadvantage. This represents an omission of one of the most important health determinants. Consideration should be given to creating codes for use by primary care practitioners.

Epigenetic ‘clocks’ based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that TIME-seq clocks are accurate and robust, enriched for polycomb repressive complex 2-regulated loci, and benchmark favorably against conventional methods despite being up to 100-fold less expensive. Using dietary treatments and gene therapy, we find that TIME-seq clocks reflect diverse interventions in multiple tissues. Finally, we develop an economical human blood clock ( R > 0.96, median error = 3.39 years) in 1,056 demographically representative individuals. These methods will enable more efficient epigenetic clock measurement in larger-scale human and animal studies.

Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD+ precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE"(induc-ible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epige-netic information is a reversible cause of aging.

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD + can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD + precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD + metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD + boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

Tagmentation-based methylation sequencing (TIME-seq) is an efficient and cost-effective solution for measuring and generating epigenetic clocks. We applied TIME-seq to over 2,800 mouse and human DNA samples to produce clocks that demonstrate accuracy and robustness; the method also outperforms conventional methods in speed and cost. The simple and practical design of TIME-seq facilitates large-scale epigenetic clock analysis, which makes it a valuable tool for advancing aging research.

Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)(+) metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD(+) metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD(+) precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD(+) precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+)-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.

BACKGROUND:Frailty is characterised by a decline in physical, cognitive, energy, and health reserves and is linked to greater functional dependency and higher social care utilisation. However, the relationship between receiving care, or receiving insufficient care among older people with different frailty status and the risk of unplanned admission to hospital for any cause, or the risk of falls and fractures remains unclear. METHODS AND FINDINGS:This study used information from 7,656 adults aged 60 and older participating in the English Longitudinal Study of Ageing (ELSA) waves 6-8. Care status was assessed through received care and self-reported unmet care needs, while frailty was measured using a frailty index. Competing-risk regression analysis was used (with death as a potential competing risk), adjusted for demographic and socioeconomic confounders. Around a quarter of the participants received care, of which approximately 60% received low levels of care, while the rest had high levels of care. Older people who received low and high levels of care had a higher risk of unplanned admission independent of frailty status. Unmet need for care was not significantly associated with an increased risk of unplanned admission compared to those receiving no care. Older people in receipt of care had an increased risk of hospitalisation due to falls but not fractures, compared to those who received no care after adjustment for covariates, including frailty status. CONCLUSIONS:Care receipt increases the risk of hospitalisation substantially, suggesting this is a group worthy of prevention intervention focus.