Longevity Papers

Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from the CALERIE randomized, controlled trial of long-term CR in healthy, nonobese humans broadly supports a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n = 218 participants during the trial. These data constitute a genomic data resource for a randomized controlled trial of an intervention targeting the biology of aging. Datasets include whole-genome single-nucleotide polymorphism genotypes, and three-timepoint-longitudinal DNA methylation, mRNA and small RNA datasets generated from blood, skeletal muscle and adipose tissue samples (total sample n = 2,327). The CALERIE Genomic Data Resource described in this article is available from the Aging Research Biobank. This multi-tissue, multi-omics, longitudinal data resource has great potential to advance translational geroscience. ClinicalTrials.gov registration: NCT00427193 .

While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter. The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.

Aging is a fundamental driver of numerous life-threatening diseases, significantly compromising cellular structures and functions, including the integrity of the nucleus. A consistent feature of aging across diverse species is the progressive accumulation of lipid droplets (nLDs) within the nuclear compartment, which disrupts nuclear architecture and functionality. Notably, aging is accompanied by a marked increase in nLD accumulation at the nuclear envelope. Interventions known to extend lifespan, such as caloric restriction and reduced insulin signaling, significantly reduce both the rate of accumulation and the size of nLDs. The triglyceride lipase ATGL-1, which localizes to the nuclear envelope, plays a critical role in limiting nLD buildup and maintaining nuclear lipid balance, especially in long-lived mutant worms. These findings establish excessive nuclear lipid deposition as a key hallmark of aging, with profound implications for nuclear processes such as chromatin organization, DNA repair, and gene regulation. In addition, ATGL-1 emerges as a promising therapeutic target for preserving nuclear health, extending organismal healthspan, and combating age-related disorders driven by lipid dysregulation.

Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced