Mechanisms Of Longevity Research Articles

EFFECTS OF APILARNIL AND QUEEN BEE LARVAE ON LARVAL MORTALITY AND LONGEVITY IN DROSOPHILA MELANOGASTER

The basic mechanisms of ageing and longevity are not yet fully understood. More studies are needed to correlate this situation with functional foods and food supplements that have been used frequently recently. Bee products are in the first place in the use of natural products and food supplements. It has been reported that drone larvae (apilarnil) and queen bee larvae, which have become popular in recent years, support the protection of health due to their high nutritional value, but no studies have been conducted on their life-extending efficacy. For this purpose, the efficacy of these two bee products on life span and mortality was investigated in our study. Apilarnil and queen bee larvae lyophilisates added to Drosophila melanogaster medium at different concentrations (0.5; 1.0; 2.5 and 5.0 mg/ml medium) were studied separately in male and female populations for treatment and control groups. As a result, apilarnil at 5 mg/ml concentration showed the best effect in terms of larval mortality compared to the control group, while the most effective group in terms of mean life span was determined as queen bee larvae with 83.1±3.53 days. In general, both bee products increased the life span of flies in parallel with the increase in concentration in both female and male populations. These results were statistically significant at p

Deciphering anhydrobiosis and plant parasitism of the wheat seed gall nematode, Anguina tritici through transcriptomic analysis

The wheat seed gall nematode (Anguina tritici L.) poses a significant threat to wheat and barley production. Central to its survival is the ability to endure desiccation through anhydrobiosis, setting it apart from other nematodes. Unraveling the molecular mechanisms governing anhydrobiosis and plant parasitism in A. tritici is crucial for devising effective management strategies. A comprehensive transcriptomic analysis was conducted to elucidate the genetic pathways involved in these processes. Employing next-generation sequencing technologies, gene expression profiling was performed across three developmental stages, namely anhydrobiotic J2, revived J2 and the adult. Transcriptomic profiling yielded 139,002 transcripts in anhydrobiotic J2s, 156,731 in revived J2s, and 80,282 in adult stages, with a cumulative assembly size of 133.2 Mb. Differential gene expression analysis revealed that 1223 genes were significantly upregulated whereas 1934 genes were downregulated in anhydrobiotic J2s in comparison to revived J2s. Comparative transcriptomic analysis across nematode species highlighted conserved and species-specific genes. Functional annotation identified key genes associated with anhydrobiosis, plant parasitism, glycosylation, and longevity mechanisms. Real-time PCR validation corroborated differential expression patterns. The present study provides gene homologs and longevity pathways, which indicate similarity of the mechanism of dauer larva formation and survival strategies to that of Caenorhabditis elegans. Comprehensive understanding of the molecular basis for survival and parasitic strategies of A. tritici, shall provide potential targets for novel control interventions to mitigate nematode's impact on wheat crops.

Gut microbiota and healthy longevity.

Recent progress on the underlying biological mechanisms of healthy longevity has propelled the field from elucidating genetic modification of healthy longevity hallmarks to defining mechanisms of gut microbiota influencing it. Importantly, the role of gut microbiota in the healthy longevity of the host may provide unprecedented opportunities to decipher the plasticity of lifespan on a natural evolutionary scale and shed light on using microbiota-targeted strategies to promote healthy aging and combat age-related diseases. This review investigates how gut microbiota affects healthy longevity, focusing on the mechanisms through which gut microbiota modulates it. Specifically, we focused on the ability of gut microbiota to enhance the intestinal barrier integrity, provide protection from inflammaging, ameliorate nutrientsensing pathways, optimize mitochondrial function, and improve defense against age-related diseases, thus participating in enhancing longevity and healthspan.

Redox dynamics in seeds of Acer spp: unraveling adaptation strategies of different seed categories.

Seeds of woody plant species, such as those in the Acer genus like Norway maple (Acer platanoides L.) and sycamore (Acer pseudoplatanus L.), exhibit unique physiological traits and responses to environmental stress. Thioredoxins (Trxs) play a central role in the redox regulation of cells, interacting with other redox-active proteins such as peroxiredoxins (Prxs), and contributing to plant growth, development, and responses to biotic and abiotic stresses. However, there is limited understanding of potential variations in this system between seeds categorized as recalcitrant and orthodox, which could provide insights into adaptive strategies. Using proteomic analysis and DDA methods we investigated the Trx-h1 target proteins in seed axes. We complemented the results of the proteomic analysis with gene expression analysis of the Trx-h1, 1-Cys-Prx, and TrxR NTRA genes in the embryonic axes of maturing, mature, and stored seeds from two Acer species. The expression of Trx-h1 and TrxR NTRA throughout seed maturation in both species was low. The expression of 1-Cys-Prx remained relatively stable throughout seed maturation. In stored seeds, the expression levels were minimal, with slightly higher levels in sycamore seeds, which may confirm that recalcitrant seeds remain metabolically active during storage. A library of 289 proteins interacting with Trx-h1 was constructed, comprising 68 from Norway maple and 221 from sycamore, with distinct profiles in each seed category. Recalcitrant seed axes displayed a wide array of metabolic, stress response, and signaling proteins, suggesting sustained metabolic activity during storage and the need to address oxidative stress. Conversely, the orthodox seed axes presented a protein profile, reflecting efficient metabolic shutdown, which contributes to their extended viability. The results of the study provide new insights into seed viability and storage longevity mechanisms. They enhance the understanding of seed biology and lay the foundation for further evolutionary research on seeds of different categories.

Nur77 improves ovarian function in reproductive aging mice by activating mitophagy and inhibiting apoptosis

Reproductive aging not only affects the fertility and physical and mental health of women but also accelerates the aging process of other organs. There is an urgent need newfor novel mechanisms, targets, and drugs to break the vicious cycle of mitochondrial dysfunction, redox imbalance, and germ cell apoptosis associated with ovarian aging. Autophagy, recognized as a longevity mechanism, has recently become a focal point in anti-aging research. Although mitophagy is a type of autophagy, its role and regulatory mechanisms in ovarian aging, particularly in age-related ovarian function decline, remain unclear. Nerve growth factor inducible gene B (Nur77) is an early response gene that can be stimulated by oxidative stress, DNA damage, metabolism, and inflammation. Recent evidence recommends that decreased expression of Nur77 is associated with age-related myocardial fibrosis, renal dysfunction, and Parkinson's disease; however, its association with ovarian aging has not been studied yet. We herein identified Nur77 as a regulator of germ cell senescence, apoptosis, and mitophagy and found that overexpression of Nur77 can activate mitophagy, improve oxidative stress, reduce apoptosis, and ultimately enhance ovarian reserve in aged mice ovaries. Furthermore, we discovered an association between Nur77 and the AKT pathway through String and molecular docking analyses. Experimental confirmation revealed that the AKT/mTOR signaling pathway is involved in the regulation of Nur77 in ovarian function. In conclusion, our results suggest Nur77 as a promising target for preventing and treating ovarian function decline related to reproductive aging.

Superoxide signal orchestrates tetrathiomolybdate-induced longevity via ARGK-1 in Caenorhabditis elegans

PurposeWhile reactive oxygen species (ROS) have been identified as key redox signaling agents contributing to aging process, which and how specific oxidants trigger healthy longevity remain unclear. This paper aimed to explore the precise role and signaling mechanism of superoxide (O2•−) in health and longevity. MethodsA tool for precise regulation of O2•− levels in vivo was developed based on the inhibition of superoxide dismutase 1 (SOD1) by tetrathiomolybdate (TM) in Caenorhabditis elegans (C. elegans). Then, we examined the effects of TM on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the signaling mechanism for longevity induced by TM-O2•− was screened by transcriptome analysis and tested in sod-1 and argk-1 RNAi strains, sod-2, sod-3, and daf-16 mutants. ResultsTM promoted longevity in C. elegans with a concomitant extension of healthy lifespan as indicated by increasing fertility and mobility and reducing lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanically, TM could precisely regulate O2•− levels in nematodes via modulating SOD1 activity. An O2•− scavenger Mn(III)TBAP abolished TM-induced lifespan extension, while an O2•− generator paraquat at low concentration mimicked the life prolongation effects. The longevity in TM-treated worms was abolished by sod-1 RNAi but was not affected in sod-2 or sod-3 mutants. Further transcriptome analysis revealed arginine kinase ARGK-1 and its downstream insulin/insulin-like growth factor 1 signaling (IIS) as potential effectors for TM-O2•‾-induced longevity, and argk-1 RNAi or daf-16 mutant nullified the longevity. ConclusionsThese findings indicate that it is feasible to precisely control specific oxidant in vivo and O2•− orchestrates TM-induced health and longevity in C. elegans via ARGK-1-IIS axis.

Specific differences and novel key regulatory genes of sex in influencing exceptional longevity phenotypes

Background and aimsAlthough the life expectancy of women systematically and robustly exceeds that of men, specific differences and molecular mechanisms of sex in influencing longevity phenotypes remain largely unknown. Therefore, we performed transcriptome sequencing of peripheral blood samples to explore regulatory mechanisms of healthy longevity by incorporating sex data. MethodsWe selected 34 exceptional longevity (age: 98.26 ± 2.45 years) and 16 controls (age: 52.81 ± 9.78) without advanced outcomes from 1363 longevity and 692 controls recruited from Nanning of Guangxi for RNA sequencing 1. The transcriptome sequencing 1 data of 50 samples were compared by longevity and sex to screen differentially expressed genes (DEGs). Then, 121 aging samples (40–110 years old) without advanced outcomes from 355 longevity and 294 controls recruited from Dongxing of Guangxi were selected for RNA sequencing 2. The genes associated with aging from the transcriptome sequencing 2 of 121 aging samples were filtered out. Finally, the gender-related longevity candidate genes and their possible metabolic pathways were verified by cell model of aging and a real-time polymerase chain reaction (RT-PCR). ResultsMetabolism differs between male and female and plays a key role in longevity. Moreover, the principal findings of this study revealed a novel key gene, UGT2B11, that plays an important role in regulating lipid metabolism through the peroxisome proliferator activated receptor gamma (PPARG) signalling pathway and ultimately improving lifespan, particularly in females. ConclusionThe findings suggest specific differences in metabolism affecting exceptional longevity phenotypes between the sexes and offer novel therapeutic targets to extend lifespan by regulating lipid homeostasis.

Aloe vera Gel Extract Prolongs Lifespan in Caenorhabditis elegans

Caenorhabditis elegans (C. elegans), with its superiority and physiological aging properties, has become a widely recognized model system in research on aging, longevity mechanisms, age-related diseases, and drug screening. Lifespan-extending mutations in C. elegans are known to slow the aging process by interfering with a number of signaling pathways such as the AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR) and insulin/IGF-1 signaling (IIS) pathways. We aimed to see how Aloe vera (A. vera) gel affects the fertilization and lifespan of C. elegans. In the presence of all A. vera gel concentrations (0.312 - 5 mg/mL), the fertilization capacity of N2 worms increased and extended their lifespan as well as increased their body size. We found that in N2 worms cultured with 2.5 mg/ml A. vera gel, sgk-1, age-1, and let-363 mRNA expression was significantly increased, while rsks-1 mRNA expression was significantly decreased. We therefore conclude that it may extend lifespan through a mechanism specifically dependent on mTOR signaling. All these observations will provide a new perspective on mammalian life extension through the model organism C. elegans.

Charting the Research Terrain for Large Old Trees: Findings from a Quantitative Bibliometric Examination in the Twenty-First Century

Despite their relatively small numbers, large old trees play disproportionately important roles in global biodiversity and ecosystem functions. There is a lack of systematic reviews and quantitative analyses of the accumulated literature. Understanding the research context and evolution could pump prime research and conservation endeavors. Using the comprehensive Web of Science, we applied VOSviewer (1.6.19) and CiteSpace (6.1R2) bibliometric software to examine the large old tree research field in 2000–2022. The queries of the bibliographic database generated quantitative–visual depictions in the form of knowledge maps. The nodes denote research intensity, and inter-node linkages denote the pathways and frequencies of collaborative activities. The research outputs differed significantly in terms of regions, countries, institutions, high-citation articles, productive researchers, hot topics, and research frontiers. Conspicuous spatial disparities were displayed, with the U.S.A., China, and Australia leading in publication counts and a cluster of European countries making considerable collective contributions. The research collaboration demonstrated a dichotomy: European countries networked more by geographical propinquity, and the top three countries connected by long-distance leap-frog jumps. The entrenched discrepancies between the endowed developed domains vis-à-vis the deprived developing domains were clearly expressed. The research productivity progressed through three stages: initial, growth, and flourishing. The leading institutions, researchers, and highly cited papers were recognized. The keyword analysis pinpointed diverse research hotspots: growth dynamics, conservation and management, ecological functions, and environmental response. This study informs recommendations for future research directions and cooperation on longevity mechanisms, evolutionary adaptation, dynamic monitoring, and temporal–spatial patterns. The integrated application of GIS, machine learning, and big data technologies could strengthen research capability.

Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity.

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMP-activated protein kinase and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin-positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk, and organism longevity.

Renin-angiotensin system gene polymorphism and aging

A personalized healthy aging program, aimed at preservation of functional capacities in old ages, should consider genetic (hereditary) factors that determine the structure and functions of body organs and systems, and their age-related changes. Individual genetic characteristics of a person can influence the aging process. For this reason, recent research focuses on identifying genetic mechanisms of aging and longevity associated with multifactorial diseases. Renin-angiotensin system (RAS) contributes to the development of pathological conditions leading to cardiovascular diseases, cognitive changes, disorders of auditory and visual analyzers, and may determine the preservation of functional capacities in older adults. We present a literature review of the role of the RAS gene polymorphisms in the aging processes. The results of the synthesis of Russian and international literature indicated the contribution of polymorphic variants of the angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1) genes to the development of pathological conditions and the associated decreases in functional capacities of an elderly person. Testing for these polymorphisms can be of a practical importance for personified health assessment and development of timely preventive interventions aimed at improving life expectancy and quality of life among older adults.

The CEPH aging cohort and biobank: a valuable collection of biological samples from exceptionally long-lived French individuals and their offspring for longevity studies

The increasing aging of the human population is currently and for the coming decades a major public health issue in many countries, requiring the implementation of global public health policies promoting healthy and successful aging. Individuals are not equal in the face of aging and some can present exceptional healthspan and/or lifespan, which are notably influenced by both genetic and environmental factors. Research and studies on human aging, healthy aging and longevity should rely in particular on cohorts of long-lived individuals, also including biological samples allowing studies on the biology of aging and longevity. In this manuscript, we provide for the first time a complete description of the CEPH (Centre d’Etude du Polymophisme Humain) Aging cohort, an exceptional cohort recruited during the 90s to 2000s, including more than 1700 French long-lived individuals (≥ 90 years old) born between 1875 and 1916 as well as for some of them their siblings and offspring. Among the participants, 1265 were centenarians, including 255 semi-supercentenarians ([105–110] years old) and 25 supercentenarians (≥ 110 years old). The available anthropometric, epidemiologic and clinical data for the cohort participants are described and especially the collection of blood-derived biological samples associated with the cohort which includes DNA, cryopreserved cells and cell lines, plasma, and serum. This biological collection from the first cohort of centenarians in the world is an inestimable resource for ongoing and future molecular, cellular, and functional studies aimed at deciphering the mechanisms of human (successful) aging and longevity.

ER CALCIUM SIGNALING COORDINATES MITOCHONDRIAL DYNAMICS AND METABOLIC FUNCTION TO PROMOTE LONGEVITY

Abstract Inter-organelle communication is a critical determinant of cellular metabolic homeostasis, and defects in the interactions between organelles are increasingly correlated with age-dependent diseases. Despite these promising links, exploration of how inter-organelle signaling pathways can be targeted to promote healthy organismal aging is a nascent area of research. We have established a foundation in C. elegans to investigate how the communication between endoplasmic reticulum (ER) and mitochondria, two of the most central metabolic hubs in cells, controls the aging process. Combining electron microscopy, live-imaging and biochemical approaches, we provide evidence that C. elegans forms ER-mitochondrial contacts and that through molecular mechanisms conserved to mammals, ER calcium flux potently stimulates mitochondrial bioenergetics. Furthermore, genetic manipulation of the ER inositol triphosphate receptor (InsP3R) reveals that ER calcium signaling promotes mitochondrial homeostasis at multiple other levels, including mitochondrial gene expression and dynamics. Building on this foundation, we now reveal that ER calcium signaling is essential for longevity in contexts of mitochondrial reprogramming. Surprisingly, InsP3R-stimulated mitochondrial bioenergetics do not appear to be the key mechanism of longevity in these contexts, but rather the underappreciated roles of the ER in tuning mitochondrial gene expression and morphology. Our results thus highlight the InsP3R as a potent and central regulator of diverse mitochondrial properties and reveal that the connections between ER and mitochondria are deeper and more complex than current models suggest. Overall, we reveal that inter-organelle communication between ER and mitochondria is an essential mechanism of longevity in paradigms involving mitochondrial reprogramming.

PROSPECTIVE MULTI-OMIC ANALYSIS OF HUMAN LONGEVITY COHORTS IDENTIFIES ANALYTE NETWORKS ASSOCIATED WITH LONGEVITY

Abstract Serum based biomarkers of longevity have long been sought to explain the mechanisms of healthy aging and longevity. Using a 1:3 case cohort design, the Longevity Consortium has produced untargeted mass spectrometry based proteomic and metabolomic datasets from serum of four cohorts with longevity status, defined as those that reached the age corresponding to the 98th percentile of survival using sex specific and birth cohort specific survival percentiles. The cohorts are the Osteoporotic Fractures in Men study, the Study of Osteoporotic Fractures, the Health, Aging, and Body Composition Study, and the Cardiovascular Health Study. In this study, we integrate metabolomics and proteomics using machine learning and system biology approaches to construct multi-omic signatures predictive of longevity and healthy aging. We identify networks enriched for biomarkers previously shown to be associated with longevity such as apolipoproteins, along with novel associations, and we further compare with our findings in a mouse omics LC dataset of molecular changes induced by life-extending interventions. We show substantial differences between male and female longevity networks. The study highlights the effectiveness of using integrative systems biology methods to capture the heterogeneity of underlying molecular aging phenotypes, in order to generate a robust signature of longevity. The identified biomarker signatures may have significant implications for the development of personalized interventions aimed at promoting healthy aging and preventing age-related diseases.

Molecular characteristics of IGF and IGF1R genes and their potential roles on longevity in two scallops with distinct lifespans

Bay scallops are commercially important bivalve species for aquaculture worldwide, but the serious inbreeding depression is decreasing their production. Some interspecific hybrids of bay scallops (Argopecten irradians irradians) and Peruvian scallops (A. purpuratus) exhibit longer lifespan and significantly larger size for high yield, which may result from the longevity genes of Peruvian scallops. Insulin-like growth factor (IGF) system, as the conspicuous entry point of insulin/insulin-like growth factor signal (IIS) pathway, regulates various cellular processes including growth, autophagy, aging and longevity, but its roles remain unexplored in marine animals. In this study, we separately cloned a unique IGF2 (ApIGF2 and AiIGF2) and IGF1R (ApIGF1R and AiIGF1R) for the first time from two closely related Argopecten scallops with distinct lifespans and characterized for their ability to regulate longevity. Sequence analysis demonstrated that there were six-span transmembrane domains located at the additional extension of C-terminus special to AiIGF2, which appeared to relate to the differences in posttranslational processing. The amino acid variation (Y247) in TyrKc domain may be a key site affecting ApIGF1R kinase activity for longevity. Spatiotemporal expression of IGF2 and IGF1R during development and aging showed that the mantle and gonad are representative tissues for aging in scallops. The dietary restriction assay revealed the beneficial effects of attenuated IGF2 and IGF1R levels on longevity in scallops. The invigorated IGF1R conferred DNA repair and prosurvival properties to Peruvian scallops for radio-resistance after acute radioresistance. Inhibition of AiIGF1R upregulated the expression of senescence-associated genes (PENT, FoxO, CAT, Mn-SOD) and antioxidant enzyme activities, and suppressed the senescence marker β-GAL activity, indicating that IGF1R was a crucial regulator for longevity in scallops. Collectively, our work would bring us closer to understanding the longevity mechanism mediated by IGF system and breeding larger and long-lived hybrids for the sustainable development of aquaculture.

Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice.

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.

Genetic and Epigenetic Mechanisms of Longevity in Forest Trees.

Trees are unique in terms of development, sustainability and longevity. Some species have a record lifespan in the living world, reaching several millennia. The aim of this review is to summarize the available data on the genetic and epigenetic mechanisms of longevity in forest trees. In this review, we have focused on the genetic aspects of longevity of a few well-studied forest tree species, such as Quercus robur, Ginkgo biloba, Ficus benghalensis and F. religiosa, Populus, Welwitschia and Dracaena, as well as on interspecific genetic traits associated with plant longevity. A key trait associated with plant longevity is the enhanced immune defense, with the increase in gene families such as RLK, RLP and NLR in Quercus robur, the expansion of the CC-NBS-LRR disease resistance families in Ficus species and the steady expression of R-genes in Ginkgo biloba. A high copy number ratio of the PARP1 family genes involved in DNA repair and defense response was found in Pseudotsuga menziesii, Pinus sylvestris and Malus domestica. An increase in the number of copies of the epigenetic regulators BRU1/TSK/MGO3 (maintenance of meristems and genome integrity) and SDE3 (antiviral protection) was also found in long-lived trees. CHG methylation gradually declines in the DAL 1 gene in Pinus tabuliformis, a conservative age biomarker in conifers, as the age increases. It was shown in Larix kaempferi that grafting, cutting and pruning change the expression of age-related genes and rejuvenate plants. Thus, the main genetic and epigenetic mechanisms of longevity in forest trees were considered, among which there are both general and individual processes.

Distinct longevity mechanisms across and within species and their association with aging

Lifespan varies within and across species, but the general principles of its control remain unclear. Here, we conducted multi-tissue RNA-seq analyses across 41 mammalian species, identifying longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. An integrative analysis uncovered shared longevity mechanisms within and across species, including downregulated Igf1 and upregulated mitochondrial translation genes, and unique features, such as distinct regulation of the innate immune response and cellular respiration. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes, involved in proteolysis and PI3K-Akt signaling. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed longevity interventions, including KU0063794, which extended mouse lifespan and healthspan. Overall, this study uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for discovering longevity interventions.

Mediterranean mechanisms of longevity.

Mediterranean mechanisms of longevity.

Mosaic Chromosomal Alterations and Human Longevity.

Mosaic chromosomal alterations (mCAs) are structural alterations associated with aging, cancer, cardiovascular disease, infectious diseases, and mortality. The distribution of mCAs in centenarians and individuals with familial longevity is poorly understood. We used MOsaic CHromosomal Alteration (MoChA) to discover mCAs in 2050 centenarians, offspring, and 248 controls from the New England Centenarian Study (NECS) and in 3 642 subjects with familial longevity and 920 spousal controls from the Long-Life Family Study (LLFS). We analyzed study-specific associations of somatic mCAs with age, familial longevity, the incidence of age-related diseases, and mortality and aggregated the results by meta-analysis. We show that the accumulation of mCAs > 100 KB increased to 102 years and plateaued at older ages. Centenarians and offspring accumulated fewer autosomal mCAs compared with controls (relative risk 0.637, p = .0147). Subjects with the APOE E4 allele had a 35.3% higher risk of accumulating autosomal mCAs (p = .002). Males were at higher risk for mCAs compared to females (male relative risk 1.36, p = 5.15e-05). mCAs were associated with increased hazard for cancer (hazard ratio 1.2) and dementia (hazard ratio 1.259) at a 10% false discovery rate. We observed a borderline significant association between mCAs and risk for mortality (hazard ratio 1.07, p = .0605). Our results show that the prevalence of individuals with mCAs does not continue to increase at ages >102 years and factors promoting familial longevity appear to confer protections from mCAs. These results suggest that limited mCA accumulation could be an important mechanism for extreme human longevity that needs to be investigated.