bims-minfam 2024-10-13 papers

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.

Keywords: cellular senescence; cognitive decline; paracrine senescence; skin aging

DOI: https://doi.org/10.1111/acel.14340

Nat Aging. 2024 Oct 07.

Optimistic versus pessimistic scenarios for future life expectancy.

Dmitri Jdanov, Domantas Jasilionis.

DOI: https://doi.org/10.1038/s43587-024-00722-z

Immunometabolism (Cobham). 2024 Oct;6(4): e00048

CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.

Connor S R Jankowski, Thomas Weichhart.

Hematopoietic stem cells (HSCs) are the multipotent progenitors of all immune cells. During aging, their regenerative capacity decreases for reasons that are not well understood. Recently, Song et al investigated the roles of two metabolic proteins in age-related HSC dysfunction: CD38 (a membrane-bound NADase) and the mitochondrial calcium uniporter that transports calcium into the mitochondrial matrix. They found that the interplay between these proteins is deranged in aged HSCs, contributing to their diminished renewal capacity. These findings implicate compromised nicotinamide adenine dinucleotide metabolism as underlying HSC dysfunction in aging.

Keywords: CD38; aging; hematopoiesis; mitochondria; mitochondrial calcium uniporter; nicotinamide adenine dinucleotide metabolism

DOI: https://doi.org/10.1097/IN9.0000000000000048

Geroscience. 2024 Oct 11.

DNA methylation drives hematopoietic stem cell aging phenotypes after proliferative stress.

Hagai Yanai, Taylor McNeely, Saipriya Ayyar, Michael Leone, Le Zong, Bongsoo Park, Isabel Beerman.

Aging of hematopoietic stem cells (HSCs) is implicated in various aging phenotypes, including immune dysfunction, anemia, and malignancies. The role of HSC proliferation in driving these aging phenotypes, particularly under stress conditions, remains unclear. Therefore, we induced forced replications of HSCs in vivo by a cyclical treatment with low-dose fluorouracil (5FU) and examined the impact on HSC aging. Our findings show that proliferative stress induces several aging phenotypes, including altered leukocyte counts, decreased lymphoid progenitors, accumulation of HSCs with high expression of Slamf1, and reduced reconstitution potential, without affecting stem cell self-renewal capacity. The divisional history of HSCs was imprinted in the DNA methylome, consistent with functional decline. Specifically, DNA methylation changes included global hypermethylation in non-coding regions and similar frequencies of hypo- and hyper-methylation at promoter regions, particularly affecting genes targeted by the PRC2 complex. Importantly, initial forced replication promoted DNA damage repair accumulated with age, but continuous proliferative stress led to the accumulation of double-strand breaks, independent of functional decline. Overall, our results suggest that HSC proliferation can drive some aging phenotypes primarily through epigenetic mechanisms, including DNA methylation changes.

Keywords: Aging; DNA damage; DNA methylation; Hematopoietic stem cells; Replicative stress

DOI: https://doi.org/10.1007/s11357-024-01360-4

Nat Aging. 2024 Oct 08.

The brain-body energy conservation model of aging.

Evan D Shaulson, Alan A Cohen, Martin Picard.

Aging involves seemingly paradoxical changes in energy metabolism. Molecular damage accumulation increases cellular energy expenditure, yet whole-body energy expenditure remains stable or decreases with age. We resolve this apparent contradiction by positioning the brain as the mediator and broker in the organismal energy economy. As somatic tissues accumulate damage over time, costly intracellular stress responses are activated, causing aging or senescent cells to secrete cytokines that convey increased cellular energy demand (hypermetabolism) to the brain. To conserve energy in the face of a shrinking energy budget, the brain deploys energy conservation responses, which suppress low-priority processes, producing fatigue, physical inactivity, blunted sensory capacities, immune alterations and endocrine 'deficits'. We term this cascade the brain-body energy conservation (BEC) model of aging. The BEC outlines (1) the energetic cost of cellular aging, (2) how brain perception of senescence-associated hypermetabolism may drive the phenotypic manifestations of aging and (3) energetic principles underlying the modifiability of aging trajectories by stressors and geroscience interventions.

DOI: https://doi.org/10.1038/s43587-024-00716-x

Nat Aging. 2024 Oct 09.

Francisco Lopera (1951-2024).

Agustín Ibáñez, Randall Bateman, Hernando Santamaria-García.

DOI: https://doi.org/10.1038/s43587-024-00735-8