Timing of TORC1 inhibition dictates Pol III involvement in Caenorhabditis elegans longevity.

Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced, extends lifespan across species. Reduction in the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in Caenorhabditis elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced, specifically in adulthood, demonstrating the importance of timing to control TOR regulated developmental versus adult programs. In addition, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.

Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.

A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.

Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.

The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway.

Genomic Frequencies of Dynamic DNA Sequences and Mammalian Lifespan.

BACKGROUND/AIM: Dynamic DNA sequences (i.e. sequences capable of forming hairpins, G-quadruplexes, i-motifs, and triple helices) can cause replication stress and associated mutations. One example of such a sequence occurs in the RACK7 gene in human DNA. Since this sequence forms i-motif structures at neutral pH that cause replication stress and result in spontaneous deletions in prostate cancer cells, our initial aim was to determine its potential utility as a biomarker of prostate cancer. MATERIALS AND METHODS: We cloned and sequenced the region in RACK7 where i-motif deletions often occur in DNA obtained from eight individuals. Expressed prostatic secretions were obtained from three individuals with a positive biopsy for prostate cancer and two with individuals with a negative biopsy for prostate cancer. Peripheral blood specimens were obtained from two control healthy bone marrow donors and a marrow specimen was obtained from a third healthy marrow donor. Follow-up computer searches of the genomes of 74 mammalian species available at the NCBI ftp site or frequencies of 6 dynamic sequences known to produce mutations or replication stress using a program written in Mathematica were subsequently performed. RESULTS: Deletions were found in RACK7 in specimens from both older normal adults, as well as specimens from older patients with cancer, but not in the youngest normal adult. The deletions appeared to show a weak trend to increasing frequency with patient age. This suggested that endogenous mutations associated with dynamic sequences might accumulate during aging and might serve as biomarkers of biological age rather than direct biomarkers of cancer. To test that hypothesis, we asked whether or not the genomic frequencies of several dynamic sequences known to produce replication stress or mutations in human DNA were inversely correlated with maximum lifespan in mammals. CONCLUSION: Our results confirm this correlation for six dynamic sequences in 74 mammalian genomes studied, thereby suggesting that spontaneously induced replication stress and mutations linked to dynamic sequence frequency may limit lifespan by limiting genome stability.

A phylogenetic method linking nucleotide substitution rates to rates of continuous trait evolution.

Genomes contain conserved non-coding sequences that perform important biological functions, such as gene regulation. We present a phylogenetic method, PhyloAcc-C, that associates nucleotide substitution rates with changes in a continuous trait of interest. The method takes as input a multiple sequence alignment of conserved elements, continuous trait data observed in extant species, and a background phylogeny and substitution process. Gibbs sampling is used to assign rate categories (background, conserved, accelerated) to lineages and explore whether the assigned rate categories are associated with increases or decreases in the rate of trait evolution. We test our method using simulations and then illustrate its application using mammalian body size and lifespan data previously analyzed with respect to protein coding genes. Like other studies, we find processes such as tumor suppression, telomere maintenance, and p53 regulation to be related to changes in longevity and body size. In addition, we also find that skeletal genes, and developmental processes, such as sprouting angiogenesis, are relevant.

Polygenic markers of survival and longevity in the antioxidant genes PON1, PON2, MTHFR, MSRA, SOD1, NQO1, and CAT in a 20-year follow-up study in the population from the Volga-Ural region.

BACKGROUND: Genetic background of healthy or pathological styles of aging and human lifespan is determined by joint gene interactions. Lucky combinations of antioxidant gene polymorphisms can result in a highly adaptive phenotype, providing a successful way to interact with external triggers. Our purpose was to identify the polygenic markers of survival and longevity in the antioxidant genes among elderly people with physiological and pathological aging. METHODS: In a 20-year follow-up study of 2350 individuals aged 18-114 years residing in the Volga-Ural region of Russia, sex-adjusted association analyses of MTHFR rs1801133, MSRA rs10098474, PON1 rs662, PON2 rs7493, SOD1 rs2070424, NQO1 rs1131341 and CAT rs1001179 polymorphic loci with longevity were carried out. Survival analysis was subsequently performed using the established single genes and gene-gene combinations as cofactors. RESULTS: The PON1 rs662*G allele was defined as the main longevity marker in women (OR = 1.44, p = 3E-04 in the log-additive model; HR = 0.77, p = 1.9E-04 in the Cox-survival model). The polymorphisms in the MTHFR, MSRA, PON2, SOD1, and CAT genes had an additive effect on longevity. A strong protective effect of combined MTHFR rs1801133*C, MSRA rs10098474*T, PON1 rs662*G, and PON2 rs7493*C alleles against mortality was obtained in women (HR = 0.81, p = 5E-03). The PON1 rs662*A allele had a meaningful impact on mortality for both long-lived men with cerebrovascular accidents (HR = 1.76, p = 0.027 for the PON1 rs662*AG genotype) and women with cardiovascular diseases (HR = 1.43, p = 0.002 for PON1 rs662*AA genotype). The MTHFR rs1801133*TT (HR = 1.91, p = 0.036), CAT rs1001179*TT (HR = 2.83, p = 0.031) and SOD1 rs2070424*AG (HR = 1.58, p = 0.018) genotypes were associated with the cancer mortality. CONCLUSION: In our longitudinal 20-year study, we found the combinations of functional polymorphisms in antioxidant genes involved in longevity and survival in certain clinical phenotypes in the advanced age.

Telomeres and aging: on and off the planet!

Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.

Microbiome composition as a potential predictor of longevity in rabbits.

BACKGROUND: Longevity and resilience are two fundamental traits for more sustainable livestock production. These traits are closely related, as resilient animals tend to have longer lifespans. An interesting criterion for increasing longevity in rabbit could be based on the information provided by its gut microbiome. The gut microbiome is essential for regulating health and plays crucial roles in the development of the immune system. The aim of this research was to investigate if animals with different longevities have different microbial profiles. We sequenced the 16S rRNA gene from soft faeces from 95 does. First, we compared two maternal rabbit lines with different longevities; a standard longevity maternal line (A) and a maternal line (LP) that was founded based on longevity criteria: females with a minimum of 25 parities with an average prolificacy per parity of 9 or more. Second, we compared the gut microbiota of two groups of animals from line LP with different longevities: females that died/were culled with two parities or less (LLP) and females with more than 15 parities (HLP). RESULTS: Differences in alpha and beta diversity were observed between lines A and LP, and a partial least square discriminant analysis (PLS-DA) showed a high prediction accuracy (> 91%) of classification of animals to line A versus LP (146 amplicon sequence variants (ASV)). The PLS-DA also showed a high prediction accuracy (> 94%) to classify animals to the LLP and HLP groups (53 ASV). Interestingly, some of the most important taxa identified in the PLS-DA were common to both comparisons (Akkermansia, Christensenellaceae R-7, Uncultured Eubacteriaceae, among others) and have been reported to be related to resilience and longevity. CONCLUSIONS: Our results indicate that the first parity gut microbiome profile differs between the two rabbit maternal lines (A and LP) and, to a lesser extent, between animals of line LP with different longevities (LLP and HLP). Several genera were able to discriminate animals from the two lines and animals with different longevities, which shows that the gut microbiome could be used as a predictive factor for longevity, or as a selection criterion for these traits.

A diet of oxidative stress-adapted bacteria improves stress resistance and lifespan in C. elegans via p38-MAPK.

Organisms across taxa face stresses including variable temperature, redox imbalance, and xenobiotics. Successfully responding to stress and restoring homeostasis are crucial for survival. Aging is associated with a decreased stress response and alterations in the microbiome, which contribute to disease development. Animals and their microbiota share their environment; however, microbes have short generation time and can rapidly evolve and potentially affect host physiology during stress. Here, we leverage Caenorhabditis elegans and its simplified bacterial diet to demonstrate how microbial adaptation to oxidative stress affects the host's lifespan and stress response. We find that worms fed stress-evolved bacteria exhibit enhanced stress resistance and an extended lifespan. Through comprehensive genetic and metabolic analysis, we find that iron in stress-evolved bacteria enhances worm stress resistance and lifespan via activation of the mitogen-activated protein kinase pathway. In conclusion, our study provides evidence that understanding microbial stress-mediated adaptations could be used to slow aging and alleviate age-related health decline.

Genetic, Environmental, and Stochastic Components of Lifespan Variability: The Drosophila Paradigm.

Lifespan is a complex quantitative trait involving genetic and non-genetic factors as well as the peculiarities of ontogenesis. As with all quantitative traits, lifespan shows considerable variation within populations and between individuals. Drosophila, a favourite object of geneticists, has greatly advanced our understanding of how different forms of variability affect lifespan. This review considers the role of heritable genetic variability, phenotypic plasticity and stochastic variability in controlling lifespan in Drosophila melanogaster. We discuss the major historical milestones in the development of the genetic approach to study lifespan, the breeding of long-lived lines, advances in lifespan QTL mapping, the environmental factors that have the greatest influence on lifespan in laboratory maintained flies, and the mechanisms, by which individual development affects longevity. The interplay between approaches to study ageing and lifespan limitation will also be discussed. Particular attention will be paid to the interaction of different types of variability in the control of lifespan.

iMPAQT reveals that adequate mitohormesis from TFAM overexpression leads to life extension in mice.

Mitochondrial transcription factor A, TFAM, is essential for mitochondrial function. We examined the effects of overexpressing the TFAM gene in mice. Two types of transgenic mice were created: TFAM heterozygous (TFAM Tg) and homozygous (TFAM Tg/Tg) mice. TFAM Tg/Tg mice were smaller and leaner notably with longer lifespans. In skeletal muscle, TFAM overexpression changed gene and protein expression in mitochondrial respiratory chain complexes, with down-regulation in complexes 1, 3, and 4 and up-regulation in complexes 2 and 5. The iMPAQT analysis combined with metabolomics was able to clearly separate the metabolomic features of the three types of mice, with increased degradation of fatty acids and branched-chain amino acids and decreased glycolysis in homozygotes. Consistent with these observations, comprehensive gene expression analysis revealed signs of mitochondrial stress, with elevation of genes associated with the integrated and mitochondrial stress responses, including Atf4, Fgf21, and Gdf15. These found that mitohormesis develops and metabolic shifts in skeletal muscle occur as an adaptive strategy.

Genomic signatures of exceptional longevity and negligible aging in the long-lived red sea urchin.

The red sea urchin (Mesocentrotus franciscanus) is one of the Earth's longest-living animals, reported to live more than 100 years with indeterminate growth, life-long reproduction, and no increase in mortality rate with age. To understand the genetic underpinnings of longevity and negligible aging, we constructed a chromosome-level assembly of the red sea urchin genome and compared it to that of short-lived sea urchin species. Genome-wide syntenic alignments identified chromosome rearrangements that distinguish short- and long-lived species. Expanded gene families in long-lived species play a role in innate immunity, sensory nervous system, and genome stability. An integrated network of genes under positive selection in the red sea urchin was involved in genomic regulation, mRNA fidelity, protein homeostasis, and mitochondrial function. Our results implicated known longevity genes in sea urchin longevity but also revealed distinct molecular signatures that may promote long-term maintenance of tissue homeostasis, disease resistance, and negligible aging.

Using genetics and proteomics data to identify proteins causally related to COVID-19, healthspan and lifespan: a Mendelian randomization study.

BACKGROUND: COVID-19 pandemic poses a heavy burden on public health and accounts for substantial mortality and morbidity. Proteins are building blocks of life, but specific proteins causally related to COVID-19, healthspan and lifespan have not been systematically examined. METHODS: We conducted a Mendelian randomization study to assess the effects of 1,361 plasma proteins on COVID-19, healthspan and lifespan, using large GWAS of severe COVID-19 (up to 13,769 cases and 1,072,442 controls), COVID-19 hospitalization (32,519 cases and 2,062,805 controls) and SARS-COV2 infection (122,616 cases and 2,475,240 controls), healthspan (n = 300,477) and parental lifespan (~0.8 million of European ancestry). RESULTS: We identified 35, 43, and 63 proteins for severe COVID, COVID-19 hospitalization, and SARS-COV2 infection, and 4, 32, and 19 proteins for healthspan, father's attained age, and mother's attained age. In addition to some proteins reported previously, such as SFTPD related to severe COVID-19, we identified novel proteins involved in inflammation and immunity (such as ICAM-2 and ICAM-5 which affect COVID-19 risk, CXCL9, HLA-DRA and LILRB4 for healthspan and lifespan), apoptosis (such as FGFR2 and ERBB4 which affect COVID-19 risk and FOXO3 which affect lifespan) and metabolism (such as PCSK9 which lowers lifespan). We found 2, 2 and 3 proteins shared between COVID-19 and healthspan/lifespan, such as CXADR and LEFTY2, shared between severe COVID-19 and healthspan/lifespan. Three proteins affecting COVID-19 and seven proteins affecting healthspan/lifespan are targeted by existing drugs. CONCLUSIONS: Our study provided novel insights into protein targets affecting COVID-19, healthspan and lifespan, with implications for developing new treatment and drug repurposing.

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

[Genetics, epigenetics, and environmental factors in life expectancy-What role does nature-versus-nurture play in aging?] / Genetik, Epigenetik und Umweltfaktoren der Lebenserwartung ­ Welche Rolle spielt Nature-versus-Nurture beim Altern?

In Germany and worldwide, the average age of the population is continuously rising. With this general increase in chronological age, the focus on biological age, meaning the actual health and fitness status, is becoming more and more important. The key question is to what extent the age-related decline in fitness is genetically predetermined or malleable by environmental factors and lifestyle.Many epigenetic studies in aging research have provided interesting insights in this nature-versus-nurture debate. In most model organisms, aging is associated with specific epigenetic changes, which can be countered by certain interventions like moderate caloric restriction or increased physical activity. Since these interventions also have positive effects on lifespan and health, epigenetics appears to be the interface between environmental factors and the aging process. This notion is supported by the fact that an epigenetic drift occurs through the life course of identical twins, which is related to the different manifestations of aging symptoms. Furthermore, biological age can be determined with high precision based on DNA methylation patterns, further emphasizing the importance of epigenetics in aging.This article provides an overview of the importance of genetic and epigenetic parameters for life expectancy. A major focus will be on the possibilities of maintaining a young epigenome through lifestyle and environmental factors, thereby slowing down biological aging.

Meta-analysis of the transcriptome identifies aberrant RNA processing as common feature of aging in multiple species.

Aging is accompanied by the gradual deregulation of the transcriptome. However, whether age-dependent changes in the transcriptome are evolutionarily conserved or diverged remains largely unexplored. Here, we performed a meta-analysis examining the age-dependent changes in the transcriptome using publicly available datasets of 11 representative metazoans, ranging from Caenorhabditis elegans to humans. To identify the transcriptomic changes associated with aging, we analyzed various aspects of the transcriptome, including genome composition, RNA processing, and functional consequences. The use of introns and novel splice sites tended to increase with age, particularly in the brain. In addition, our analysis suggests that the age-dependent accumulation of premature termination codon-containing transcripts is a common feature of aging across multiple animal species. Using C. elegans as a test model, we showed that several splicing factors that are evolutionarily conserved and age-dependently downregulated were required to maintain a normal lifespan. Thus, aberrant RNA processing appears to be associated with aging and a short lifespan in various species.

How calorie restriction slows aging: an epigenetic perspective.

Genomic instability and epigenetic alterations are some of the prominent factors affecting aging. Age-related heterochromatin loss and decreased whole-genome DNA methylation are associated with abnormal gene expression, leading to diseases and genomic instability. Modulation of these epigenetic changes is crucial for preserving genomic integrity and controlling cellular identity is important for slowing the aging process. Numerous studies have shown that caloric restriction is the gold standard for promoting longevity and healthy aging in various species ranging from rodents to primates. It can be inferred that delaying of aging through the main effector such as calorie restriction is involved in cellular identity and epigenetic modification. Thus, an understanding of aging through calorie restriction may seek a more in-depth understanding. In this review, we discuss how caloric restriction promotes longevity and healthy aging through genomic stability and epigenetic alterations. We have also highlighted how the effectors of caloric restriction are involved in modulating the chromatin-based barriers.

Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan.

The genetic pathways that modulate ageing in multicellular organisms are typically highly conserved across wide evolutionary distances. Recently RNA polymerase III (Pol III) was shown to promote ageing in yeast, C. elegans and D. melanogaster. In this study we investigated the role of Pol III in mammalian ageing using C57BL/6N mice heterozygous for Pol III (Polr3b+/-). We identified sexually dimorphic, organ-specific beneficial as well as detrimental effects of the Polr3b+/- mutation on health. Female Polr3b+/- mice displayed improved bone health during ageing, but their ability to maintain an effective gut barrier function was compromised and they were susceptible to idiopathic dermatitis (ID). In contrast, male Polr3b+/- mice were lighter than wild-type (WT) males and had a significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b+/- mice were long-lived compared to WT controls. Overall, we find no evidence that a reduced Pol III activity extends mouse lifespan but we do find some potential organ- and sex-specific benefits for old-age health.

NUCB1 is required for proper insulin signaling to control longevity in Drosophila.

AIM: We examined the novel role of NUCB1(Nucleobindin-1) associated with longevity in Drosophila melanogaster. METHODS: We measured the lifespan, metabolic phenotypes, and mRNA levels of Drosophila insulin-like peptides (Dilps), the protein level of phosphorylated AKT, and the localization of FOXO and its target gene expressions in the NUCB1 knockdown condition. RESULTS: NUCB1 knockdown flies show an extended lifespan and metabolic phenotypes such as increased circulating glucose level and starvation resistance. The mRNA expression levels of Dilps and the protein level of phosphorylated AKT, a downstream component of insulin signaling, were decreased in NUCB1 knockdown flies compared with the control flies. Also, the nuclear localization of FOXO and its target gene expressions, such as d4E-BP and InR, were elevated. CONCLUSIONS: The results show that NUCB1 knockdown flies exhibits an extended lifespan. These findings suggest that NUCB1 modulates longevity through insulin signaling in Drosophila. Geriatr Gerontol Int 2024; 24: 486-492.