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Frailty is classically associated with advanced age but is also an important predictor of clinical outcomes in comparatively young adults with cirrhosis. We examined the association of biological aging with frailty and post-transplant outcomes in a pilot of adults with cirrhosis undergoing liver transplantation (LT). Frailty was measured via the Liver Frailty Index (LFI). The primary epigenetic clock DNA methylation (DNAm) PhenoAge was calculated from banked peripheral blood mononuclear cells; we secondarily explored two first-generation clocks (Hannum; Horvath) and two additional second-generation clocks (GrimAge; GrimAge2). Twelve adults were included: seven frail (LFI ≥ 4.4, mean age 55 years) and five robust (LFI

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Alzheimer's disease (AD) and Alzheimer's related diseases (ADRD) are prevalent age-related neurodegenerative disorders characterized by the accumulation of amyloid-β (Aβ) plaques and Tau neurofibrillary tangles. The nematode Caenorhabditis elegan s ( C. elegans ) serves as an invaluable model organism in diseases of old age-due to its rapid aging. Here we performed an unbiased systems analysis of a C. elegans strain expressing both Aβ and Tau proteins within neurons. We set out to determine if there was a phenotypic interaction between Aβ and Tau. In addition, we were interested in determining the temporal order of the phenotypic and multi-omic (geromic) outcomes. At an early stage of adulthood, we observed reproductive impairments and mitochondrial dysfunction consistent with disruptions in mRNA transcript abundance, protein solubility, and metabolite levels. Notably, the expression of these neurotoxic proteins exhibited a synergistic effect, leading to accelerated aging. Our findings shed light on the close relationship between normal aging and ADRD. Specifically, we demonstrate alterations to metabolic functions preceding age-related neurotoxicity, offering a resource for the development of new therapeutic strategies.