Gil Atzmon

The exon 3 deletion polymorphism in the growth hormone receptor gene (d3GHR) is associated with altered GH signaling and longevity-related phenotypes, yet its relationship with blood-based epigenetic aging remains unclear. We analyzed whole-blood DNA from 21 unrelated adults recruited at Laniado Medical Center to determine whether the d3GHR genotype was associated with differential DNA methylation in skin-aging-related genes and altered age acceleration across established DNA methylation clocks. Genome-wide methylation was profiled using the Infinium MethylationEPIC v2.0 array, focusing on 1098 CpG sites linked to wrinkling, pigmentation, and extracellular matrix remodeling. No significant single-CpG methylation differences were detected within the targeted panel. However, two promoter-proximal differentially methylated regions (DMRs) were identified near CYP1A1 (FWER = 0.014) and ACAT2 (FWER = 0.026). Notably, only the pan-tissue Horvath clock showed a significant genotype effect, with marked age acceleration in d3/d3 carriers (mean Δ ≈ +14.5 years, p = 0.0179) that persisted after adjustment for chronological age. In contrast, second-generation clocks such as PhenoAge showed a non-significant trend toward deceleration. These findings suggest a preliminary association between d3GHR genotype, clock-specific epigenetic age acceleration and promoter-level methylation signatures near metabolic and stress-response genes. The observed Horvath acceleration may reflect systemic metabolic or immune adaptation rather than direct structural senescence in core skin-aging gene programs in blood. Given the very small d3/d3 subgroup, these findings should be interpreted strictly as exploratory pilot observations and cannot establish reproducible genotype-specific effects without validation in larger independent cohorts.

With global life expectancy steadily rising, promoting healthy aging is becoming a critical objective of public health. Physical function tends to decline gradually, often beginning in midlife, when subtle changes start to occur and accumulate undetected until later years. This study examines the feasibility of using DNA methylation-based epigenetic clocks as biomarkers for cumulative physical performance in 24 community-dwelling adults aged 39 years and older. Our findings reveal that several epigenetic age estimators, particularly DNAmAgeHannum, are significantly associated with a novel composite score criterion derived from standardized motor function assessments (DNAmAge: ρ = −0.48, p < 0.026; DNAmPhenoAge: ρ = −0.48, p < 0.026) with DNAmAgeHannum (ρ = −0.59, p < 0.005). These findings support the potential of using epigenetic aging markers to detect early physiological decline, even in relatively healthy, midlife populations, offering a promising tool for the early identification of age-related functional deterioration.

Aging is a complex biological process marked by a progressive decline in cellular function, leading to age-related diseases such as neurodegenerative disorders, cancer, and cardiovascular diseases. Despite significant advancements in aging research, finding effective interventions to decelerate aging remains a challenge. This review explores microgravity as a novel therapeutic approach to combat aging and promote healthy longevity. The hallmarks of aging, including genomic instability, telomere shortening, and cellular senescence, form the basis for understanding the molecular mechanisms behind aging. Interestingly, microgravity has been shown to accelerate aging-like processes in model organisms and human tissues, making it an ideal environment for studying aging mechanisms in an accelerated manner. Spaceflight studies, such as NASA’s Twins Study and experiments aboard the International Space Station (ISS), reveal striking parallels between the physiological changes induced by microgravity and those observed in aging populations, including muscle atrophy, bone density loss, cardiovascular deconditioning, and immune system decline in a microgravity environment. However, upon microgravity recovery, cellular behavior, gene expression, and tissue regeneration were seen, providing vital insights into aging mechanisms and prospective therapeutic approaches. This review examines the potential of microgravity-based technologies to pioneer novel strategies for decelerating aging and enhancing healthspan under natural gravity, paving the way for breakthroughs in longevity therapies.

On October 28–31, 2024, there took place the international conference, “Longevity Nation 2024— Enhancing Research, Development and Education for Healthy Longevity” in Bar-Ilan University, Ramat Gan, Israel (http://www.longevitynation.org/). This conference explored the challenges that rise from population aging, from interdisciplinary perspectives that reflect new science and technology, and many social, cultural, political, economic and philosophical concerns that aging raises. By bringing together leading Israeli and international voices in the longevity space—researchers, developers, investors, educators, decision makers and public figures—the Longevity Nation conference aimed to contribute to increasing the synergy of science, technology and aging society, and help advance ethical scientific and technological solutions for healthy longevity for the benefit of the entire society. As the conference emphasized, in this period of conflict in Israel and the Middle East, it is especially important to build up international collaboration as a basis for future positive development.

The Druze are a distinct group known for their close community, traditions, and consanguineous marriages, dating back to the eleventh century. This practice has led to unique genetic variations, impacting both pathology and gene-associated phenotypes. Some Druze clans, particularly those with exceptional long-lived family heads (ELLI), attracted attention. Given that the bulk of these ELLI were men, the d3GHR polymorphism was the first obvious possibility. Among the 73 clan members, 8.2% carried the d3GHR isoform, with nearly 11% being males. There was a significant age-related increase (p = 0.04) in this isoform among males, leading to examination of potential environmental mediators affecting gene regulation among these carriers during life (namely epigenetic). We focused on DNA methylation due to its crucial role in gene regulation, development, and disease progression. We analyzed DNA samples from 14 clan members with different GHR genotypes, finding a significant (p < 0.05) negative correlation between DNA methylation levels and age. Employing a biological age clock, we observed a significant + 4.229 years favoring the d3GHR group over the WT and heterozygous groups. In conclusion, this study highlights the advantage of d3GHR carriers among this unique Druze clan and underscores the importance of genotype-environment interaction in epigenetic regulation and its impact on health.

The aging process, or senescence, is characterized by age-specific decline in physical and physiological function, and increased frailty and genomic changes, including mutation accumulation. However, the mechanisms through which changes in genomic architecture influence human longevity have remained obscure. Copy number variants (CNVs), an abundant class of genomic variants, offer unique opportunities for understanding age-related genomic changes. Here we report the spectrum of CNVs in a cohort of 670 Ashkenazi Jewish centenarians, their progeny, and unrelated controls. The average ages of these groups were 97.4 ± 2.8, 69.2 ± 9.2, and 66.5 ± 7.0 respectively. For the first time, we compared different size classes of CNVs, from 1 kB to 100 MB in size. Using a high-resolution custom Affymetrix array, targeting 44,639 genomic regions, we identified a total of 12,166, 22,188, and 10,285 CNVs in centenarians, their progeny, and control groups, respectively. Interestingly, the offspring group showed the highest number of unique CNVs, followed by control and centenarians. While both gains and losses were found in all three groups, centenarians showed a significantly higher average number of both total gains and losses relative to their controls (p < 0.0327, 0.0182, respectively). Moreover, centenarians showed a lower total length of genomic material lost, suggesting that they may maintain superior genomic integrity over time. We also observe a significance fold increase of CNVs among the offspring, implying greater genomic integrity and a putative mechanism for longevity preservation. Genomic regions that experienced loss or gains appear to be distributed across many sites in the genome and contain genes involved in DNA transcription, cellular transport, developmental pathways, and metabolic functions. Our findings suggest that the exceptional longevity observed in centenarians may be attributed to the prolonged maintenance of functionally important genes. These genes are intrinsic to specific genomic regions as well as to the overall integrity of the genomic architecture. Additionally, a strong association between longer CNVs and differential gene expression observed in this study supports the notion that genomic integrity could positively influence longevity.

The highly polygenic nature of human longevity renders cross-trait pleiotropy an indispensable feature of its genetic architecture. Leveraging the genetic correlation between the aging-related traits (ARTs), we sought to model the additive variance in lifespan as a function of cumulative liability from pleiotropic segregating variants. We tracked allele frequency changes as a function of viability across different age bins and prioritized 34 variants with an immediate implication on lipid metabolism, body mass index (BMI), and cognitive performance, among other traits, revealed by PheWAS analysis in the UK Biobank. Given the highly complex and non-linear interactions between the genetic determinants of longevity, we reasoned that a composite polygenic score would approximate a substantial portion of the variance in lifespan and developed the integrated longevity genetic scores ( iLGSs ) for distinguishing exceptional survival. We showed that coefficients derived from our ensemble model could potentially reveal an interesting pattern of genomic pleiotropy specific to lifespan. We assessed the predictive performance of our model for distinguishing the enrichment of exceptional longevity among long-lived individuals in two replication cohorts and showed that the median lifespan in the highest decile of our composite prognostic index is up to 4.8 years longer. Finally, using the proteomic correlates of iLGS , we identified protein markers associated with exceptional longevity irrespective of chronological age and prioritized drugs with repurposing potentials for gerotherapeutics. Together, our approach demonstrates a promising framework for polygenic modeling of additive liability conferred by ARTs in defining exceptional longevity and assisting the identification of individuals at higher risk of mortality for targeted lifestyle modifications earlier in life. Furthermore, the proteomic signature associated with iLGS highlights the functional pathway upstream of the PI3K-Akt that can be effectively targeted to slow down aging and extend lifespan.

Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the GH receptor (GHR), which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR isoform, which lacks exon 3 has recently been related to longevity; individuals carrying this isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the wild type (WT) isoform (flGHR). Further, studies performed in patients with acromegaly, Prader–Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR isoform may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject.