As average life span and elderly people prevalence in the western world population is gradually increasing, the incidence of age-related diseases such as cancer, heart diseases, diabetes, and dementia is increasing, bearing social and economic consequences worldwide. Understanding the molecular basis of aging-related processes can help extend the organism’s health span, i.e., the life period in which the organism is free of chronic diseases or decrease in basic body functions. During the last few decades, immense progress was made in the understanding of major components of aging and healthy aging biology, including genomic instability, telomere attrition, epigenetic changes, proteostasis, nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and intracellular communications. This progress has been made by three spear-headed strategies: in vitro (cell and tissue culture from various sources), in vivo (includes diverse model and non-model organisms), both can be manipulated and translated to human biology, and the study of aging-like human syndromes and human populations. Herein, we will focus on current repository of genomic “senescence” stage of aging, which includes health decline, structural changes of the genome, faulty DNA damage response and DNA damage, telomere shortening, and epigenetic alterations. Although aging is a complex process, many of the “hallmarks” of aging are directly related to DNA structure and function. This review will illustrate the variety of these studies, done in in vitro, in vivo and human levels, and highlight the unique potential and contribution of each research level and eventually the link between them.

The d3-GHR genetic variant polymorphism modulates GH responsiveness throughout life span and positively affects male longevity.

Exceptionally long-lived individuals (ELLI) who are the focus of many healthy longevity studies around the globe are now being studied in Israel. The Israeli Multi-Ethnic Centenarian Study (IMECS) cohort is utilized here for assessment of various DNA methylation clocks. Thorough phenotypic characterization and whole blood samples were obtained from ELLI, offspring of ELLI, and controls aged 53–87 with no familial exceptional longevity. DNA methylation was assessed using Illumina MethylationEPIC Beadchip and applied to DNAm age online tool for age and telomere length predictions. Relative telomere length was assessed using qPCR T/S (Telomere/Single copy gene) ratios. ELLI demonstrated juvenile performance in DNAm age clocks and overall methylation measurement, with preserved cognition and relative telomere length. Our findings suggest a favorable DNA methylation profile in ELLI enabling a slower rate of aging in those individuals in comparison to controls. It is possible that DNA methylation is a key modulator of the rate of aging and thus the ELLI DNAm profile promotes healthy longevity.

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

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Sea urchins are a minor class of marine invertebrates that share genetic similarities with humans. For example, the sea urchin species Strongylocentrotus purpuratus is estimated to have 23,300 genes in which the majority of vertebrate gene families are enveloped. Some of the sea urchin species can demonstrate extreme longevity, such as Mesocentrotus franciscanus, living for well over 100 years. Comparing human to sea urchin aging suggests that the latter do not fit within the classic understanding of biological aging, as both long- and short-lived sea urchin species demonstrate negligible senescence. Sea urchins are highly regenerative organisms. Adults can regenerate external appendages and can maintain their regenerative abilities throughout life. They grow indeterminately and reproduce throughout their entire adult life. Both long- and short-lived species do not exhibit age-associated telomere shortening and display telomerase activity in somatic tissues regardless of age. Aging S. purpuratus urchins show changes in expression patterns of protein coding genes that are involved in several fundamental cellular functions such as the ubiquitin-proteasome system, signaling pathways, translational regulation, and electron transport chain. Sea urchin longevity and senescence research is a new and promising field that holds promise for the understanding of aging in vertebrates and can increase our understanding of human longevity and of healthy aging.

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