The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age DOI Creative Commons
Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 31, 2024

Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy ameliorating disease conditions mitochondrial dysfunction across both clinical pre-clinical models. ELAM is proposed to restore bioenergetic by stabilizing inner membrane structure increasing oxidative phosphorylation coupling efficiency. Although treatment effectively attenuates physiological declines multiple tissues rodent aging models, it remains unclear whether these functional improvements correlate favorable changes molecular biomarkers of aging. Herein, we investigated the impact 8-week on pre- post- measures C57BL/6J mice frailty, muscle, function, coupled post-treatment assessments biological age affected pathways. We found that health status, as measured frailty index, strain, diastolic force significantly diminished age, changing sex-dependent manner. Conversely, mitigated accumulation was able partially reverse declines, evidenced treatment-induced increases strain fatigue resistance. Despite improvements, did not detect statistically significant gene expression or DNA methylation profiles indicative reorganization reduced most ELAM-treated groups. However, pathway analyses revealed showed pro-longevity shifts such upregulation genes involved fatty acid metabolism, translation phosphorylation, downregulation inflammation. Together, results indicate effective at mitigating signs sarcopenia heart failure an mouse model, but occur independently detectable epigenetic transcriptomic age. Thus, some age-related may be uncoupled from

Язык: Английский

Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems DOI
Ludger J.E. Goeminne, Anastasiya V. Vladimirova, Alec Eames

и другие.

Cell Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

Процитировано

9
BayesAge 2.0: a maximum likelihood algorithm to predict transcriptomic age DOI Creative Commons
Lajoyce Mboning, Emma K. Costa, Jingxun Chen

и другие.

GeroScience, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Abstract Aging is a complex biological process influenced by various factors, including genetic and environmental influences. In this study, we present BayesAge 2.0, an upgraded version of our maximum likelihood algorithm designed for predicting transcriptomic age (tAge) from RNA-seq data. Building on the original framework, which was developed epigenetic prediction, 2.0 integrates Poisson distribution to model count-based gene expression data employs LOWESS smoothing capture nonlinear gene-age relationships. provides significant improvements over traditional linear models, such as Elastic Net regression. Specifically, it addresses issues bias in predictions, with minimal age-associated observed residuals. Its computational efficiency further distinguishes reference construction cross-validation are completed more quickly compared regression, requires extensive hyperparameter tuning. Overall, represents step forward tAge offering robust, accurate, efficient tool aging research biomarker development.

Язык: Английский

Процитировано

1
The Mitochondria‐Targeted Peptide Therapeutic Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging Without Detectable Changes in Tissue Epigenetic or Transcriptomic Age DOI Creative Commons
Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy

и другие.

Aging Cell, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

ABSTRACT Aging‐related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria‐targeted peptide, has demonstrated broad therapeutic efficacy ameliorating disease conditions mitochondrial dysfunction across both clinical pre‐clinical models. Herein, we investigated the impact of 8‐week ELAM treatment on pre‐ post‐measures C57BL/6J mice frailty, muscle, function, coupled post‐treatment assessments biological age affected molecular pathways. We found that health status, as measured by frailty index, strain, diastolic force, is significantly diminished age, force changing sex‐dependent manner. Conversely, mitigated accumulation was able to partially reverse these declines, evidenced treatment‐induced increases strain fatigue resistance. Despite improvements, did not detect statistically significant changes gene expression or DNA methylation profiles indicative reorganization reduced most ELAM‐treated groups. However, pathway analyses revealed showed pro‐longevity shifts expression, such upregulation genes involved fatty acid metabolism, translation, oxidative phosphorylation, downregulation inflammation. Together, results indicate effective at mitigating signs sarcopenia an aging mouse model, but functional improvements occur independently detectable epigenetic transcriptomic age. Thus, some age‐related may be uncoupled from

Язык: Английский

Процитировано

0
Invigorating discovery and clinical translation of aging biomarkers DOI

Erik Jacques,

Chiara Herzog, Kejun Ying

и другие.

Nature Aging, Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

Язык: Английский

Процитировано

0
High-dimensional Ageome Representations of Biological Aging across Functional Modules DOI Creative Commons
Kejun Ying, Alexander Tyshkovskiy, Qingwen Chen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 21, 2024

Abstract The aging process involves numerous molecular changes that lead to functional decline and increased disease mortality risk. While epigenetic clocks have shown accuracy in predicting biological age, they typically provide single estimates for the samples lack mechanistic insights. In this study, we challenge paradigm can be sufficiently described with a age estimate. We describe Ageome, computational framework measuring of thousands pathways simultaneously mice humans. Ageome is based on premise an organism’s overall approximated by collective ages its modules, which may at different rates ages. show that, unlike conventional clocks, provides high-dimensional representation across cellular functions, enabling comprehensive assessment dynamics within individual, population, species. Application longevity intervention models revealed distinct patterns pathway-specific deceleration. Notably, cell reprogramming, while rejuvenating cells, also accelerated some modules. When applied human cohorts, demonstrated heterogeneity predictive power risk, modules showed better performance onset age-related diseases, especially cancer, compared existing clocks. Together, offers interpretable approach assessing aging, providing insights into mechanisms targets intervention.

Язык: Английский

Процитировано

2
Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer DOI Open Access
Aaron Havas, Kathryn Lande,

Adarsh Rajesh

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 3, 2024

Abstract Age is a major risk factor for liver cancer, as the case most adult human cancers. However, underlying mechanisms are not well defined. A better understanding of role aging in and other cancers can facilitate approaches assessment, early detection prevention. We hypothesize that age-driven changes render aged more sensitive to oncogenic stress hence tumorigenesis. To investigate how with age, we documented immune profile, transcriptome epigenome healthy livers from both young mice, revealing pronounced alterations aging. Notably, hepatocytes, identified heightened interferon (IFN) signaling, simultaneous tumor suppressor oncogene signaling at bulk single cell level, suggestive an poised neoplasia. challenge this seemingly state, employed adeno-associated virus (AAV)-mediated expression c-Myc mouse hepatocytes vivo . Analysis expressing revealed further elevated IFN Stimulated Genes (ISGs). This ISG upregulation was evident multiple models transformation older mice also observed humans Metabolic dysfunction-Associated Steatohepatitis (MASH). determined Stat1 necessary sufficient age specific old wild type mice. Remarkably, inhibiting Jak/Stat alongside ectopic led high-grade hepatocyte dysplasia formation, selectively Together, these results suggest state “precarious balance”, due concurrent activation pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent has been many tissues recent studies have demonstrated its detrimental consequences on aging, raising question why IFN-signaling activated during propose intrinsically higher cancer age-dependent adaptive process protect tumorigenesis, one maladaptive consequences.

Язык: Английский

Процитировано

0
Depletion of loss-of-function germline mutations in centenarians reveals longevity genes DOI Creative Commons
Kejun Ying, José Pedro Castro, Anastasia V. Shindyapina

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 19, 2024

While previous studies identified common genetic variants associated with longevity in centenarians, the role of rare loss-of-function (LOF) mutation burden remains largely unexplored. Here, we investigated LOF mutations Ashkenazi Jewish individuals from Longevity Genes Project and LonGenity study cohorts using whole-exome sequencing data. We found that centenarians had a significantly lower (11-22%) compared to controls. Similar effects were also observed their offspring. Gene-level analysis 35 genes depleted 14 these validated UK Biobank. Mendelian randomization multi-omic analyses on RGP1, PCNX2, ANO9 as consistent causal multiple aging-related traits altered expression during aging. Our findings suggest protective background, characterized by reduced damaging variants, contributes exceptional longevity, likely acting concert specific promote healthy Previous have linked but impact unclear. authors show carry fewer harmful identify may contribute extreme aging

Язык: Английский

Процитировано

0
The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age DOI Creative Commons
Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 31, 2024

Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy ameliorating disease conditions mitochondrial dysfunction across both clinical pre-clinical models. ELAM is proposed to restore bioenergetic by stabilizing inner membrane structure increasing oxidative phosphorylation coupling efficiency. Although treatment effectively attenuates physiological declines multiple tissues rodent aging models, it remains unclear whether these functional improvements correlate favorable changes molecular biomarkers of aging. Herein, we investigated the impact 8-week on pre- post- measures C57BL/6J mice frailty, muscle, function, coupled post-treatment assessments biological age affected pathways. We found that health status, as measured frailty index, strain, diastolic force significantly diminished age, changing sex-dependent manner. Conversely, mitigated accumulation was able partially reverse declines, evidenced treatment-induced increases strain fatigue resistance. Despite improvements, did not detect statistically significant gene expression or DNA methylation profiles indicative reorganization reduced most ELAM-treated groups. However, pathway analyses revealed showed pro-longevity shifts such upregulation genes involved fatty acid metabolism, translation phosphorylation, downregulation inflammation. Together, results indicate effective at mitigating signs sarcopenia heart failure an mouse model, but occur independently detectable epigenetic transcriptomic age. Thus, some age-related may be uncoupled from

Язык: Английский

Процитировано

0