p21 induces a senescence program and skeletal muscle dysfunction DOI Creative Commons
Davis A. Englund, Alyssa M. Jolliffe,

Zaira Aversa

et al.

Molecular Metabolism, Journal Year: 2022, Volume and Issue: 67, P. 101652 - 101652

Published: Dec. 9, 2022

Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice humans. Using a mouse model p21 overexpression (p21OE), we examined if mechanistically contributes to cellular senescence pathological features muscle. We show that induces several core properties muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, senescence-associated secretory phenotype (SASP). Furthermore, p21OE exhibit manifestations pathology, such as atrophy, fibrosis, impaired physical function when compared age-matched controls. These findings suggest alone is sufficient drive program reveal novel source loss dysfunction.

Language: Английский

Apoptotic stress causes mtDNA release during senescence and drives the SASP DOI Creative Commons
Stella Victorelli, Hanna Salmonowicz, James Chapman

et al.

Nature, Journal Year: 2023, Volume and Issue: 622(7983), P. 627 - 636

Published: Oct. 11, 2023

Abstract Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP) 1 . Mitochondria are major regulators SASP; however, underlying mechanisms have not been elucidated 2 often essential for apoptosis, cell fate distinct from cellular senescence. During widespread mitochondrial outer membrane permeabilization (MOMP) commits to die 3 Here we find that MOMP occurring in subset mitochondria is feature This process, called minority (miMOMP), requires BAX and BAK macropores enabling release DNA (mtDNA) into cytosol. Cytosolic mtDNA turn activates cGAS–STING pathway, regulator SASP. We inhibition vivo decreases inflammatory markers improves healthspan aged mice. Our results reveal apoptosis senescence regulated by similar mitochondria-dependent sublethal apoptotic stress driver provide proof-of-concept miMOMP-induced inflammation may be therapeutic route improve healthspan.

Language: Английский

Citations

256
The heterogeneity of cellular senescence: insights at the single-cell level DOI

Rachel Cohn,

Nathan Gasek, George A. Kuchel

et al.

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(1), P. 9 - 17

Published: May 20, 2022

Language: Английский

Citations

166
Chronic inflammation and the hallmarks of aging DOI Creative Commons
Jordan J. Baechle, Nan Chen, Priya Makhijani

et al.

Molecular Metabolism, Journal Year: 2023, Volume and Issue: 74, P. 101755 - 101755

Published: June 16, 2023

Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, low-grade inflammation during aging, without overt infection, is defined as "inflammaging," which associated with increased morbidity mortality in population. Emerging evidence suggests a bidirectional cyclical relationship between development age-related conditions, such cardiovascular diseases, neurodegeneration, cancer, frailty. How crosstalk other underlies biological mechanisms disease thus particular interest current geroscience research.

Language: Английский

Citations

144
The senescence-associated secretory phenotype and its physiological and pathological implications DOI
Boshi Wang, Jin Han, Jennifer H. Elisseeff

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(12), P. 958 - 978

Published: April 23, 2024

Language: Английский

Citations

136
SenNet recommendations for detecting senescent cells in different tissues DOI
Vidyani Suryadevara, Adam D. Hudgins,

Adarsh Rajesh

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(12), P. 1001 - 1023

Published: June 3, 2024

Language: Английский

Citations

79
Aging and chronic inflammation: highlights from a multidisciplinary workshop DOI Creative Commons
Danay Saavedra, Ana Laura Añé-Kourí, Nir Barzilai

et al.

Immunity & Ageing, Journal Year: 2023, Volume and Issue: 20(1)

Published: June 8, 2023

Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. entails the immune system characterized by decrease thymic output naïve lymphocytes, an accumulated chronic antigenic stress notably caused infections such as cytomegalovirus (CMV), cell senescence with acquisition inflammatory senescence-associated secretory phenotype (SASP). For this reason, due to SASP originating from other tissues, aging commonly accompanied low-grade inflammation, termed "inflammaging". After decades accumulating evidence regarding age-related processes domain now appears mature enough allow integrative reinterpretation old data. Here, we provide overview topics discussed recent workshop "Aging Chronic Inflammation" which many major players field contributed. We highlight advances systematic measurement interpretation biological markers aging, well their implications for human health longevity interventions that can be envisaged maintain or improve function older people.

Language: Английский

Citations

77
Molecular Mechanisms of Vascular Health: Insights From Vascular Aging and Calcification DOI Open Access
Nadia R. Sutton, Rajeev Malhotra, Cynthia St. Hilaire

et al.

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2022, Volume and Issue: 43(1), P. 15 - 29

Published: Nov. 22, 2022

Cardiovascular disease is the most common cause of death worldwide, especially beyond age 65 years, with vast majority morbidity and mortality due to myocardial infarction stroke. Vascular pathology stems from a combination genetic risk, environmental factors, biologic changes associated aging. The pathogenesis underlying development vascular aging, calcification in particular, still not fully understood. Accumulating data suggests that likely compounded by epigenetic modifications, including diabetes chronic kidney disease, plasticity smooth muscle cells acquire an osteogenic phenotype are major determinants age-associated calcification. Understanding molecular mechanisms modifiable risk factors regulating may inspire strategies promote healthy This article summarizes current knowledge concepts emphasis on

Language: Английский

Citations

71
Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype DOI Creative Commons
Máté Maus, Vanessa López-Polo, Lídia Mateo

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(12), P. 2111 - 2130

Published: Dec. 14, 2023

Abstract Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading fatal diseases. Senescent cells are main driver fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report cellular senescence, multiple types in mice humans characterized by the accumulation iron. We show vascular hemolytic injuries efficient triggering iron accumulation, which turn cause senescence promote fibrosis. Notably, find senescent persistently accumulate iron, even when surge extracellular has subdued. Indeed, under conditions exposed different senescence-inducing insults abundant ferritin-bound mostly within lysosomes, present high levels labile fuels generation reactive oxygen species SASP. Finally, demonstrate detection magnetic resonance imaging might allow non-invasive assessment burden kidneys patients with renal Our findings suggest plays central role fibrosis, initiating events may be independent identify metabolism potential therapeutic target for

Language: Английский

Citations

70
Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction DOI Creative Commons
Corina Amor, Inés Fernández-Maestre,

Saria Chowdhury

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(3), P. 336 - 349

Published: Jan. 24, 2024

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T targeting the senescence-associated protein urokinase plasminogen activator (uPAR), we previously showed safely young animals. now show uPAR-positive during aging be targeted with CAR cells. Treatment anti-uPAR improves exercise capacity physiological aging, it ameliorates (for example, improving glucose tolerance) aged mice high-fat diet. Importantly, single administration is sufficient achieve long-term therapeutic preventive effects.

Language: Английский

Citations

61
Guidelines for minimal information on cellular senescence experimentation in vivo DOI Creative Commons
Mikołaj Ogrodnik, Juan Carlos Acosta, Peter D. Adams

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(16), P. 4150 - 4175

Published: Aug. 1, 2024

Cellular senescence is a cell fate triggered in response to stress and characterized by stable cell-cycle arrest hypersecretory state. It has diverse biological roles, ranging from tissue repair chronic disease. The development of new tools study vivo paved the way for uncovering its physiological pathological roles testing senescent cells as therapeutic target. However, lack specific broadly applicable markers makes it difficult identify characterize tissues living organisms. To address this, we provide practical guidelines called "minimum information cellular experimentation vivo" (MICSE). presents an overview rodent tissues, transgenic models, non-mammalian systems, human tumors their use identification specification cells. These uniform, state-of-the-art, accessible toolset improve our understanding vivo.

Language: Английский

Citations

58