Fat Tissue, Aging, and Cellular Senescence

By T. Tchkonia, D. Morbeck, T. von Zglinicki, J. V. van Deursen, J. Lustgarten, H. Scrable, S. Khosla, M. Jensen, J. Kirkland. Aging Cell, 2010

1,048 citations recorded by the source corpus.

Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age‐related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro‐inflammatory, tissue‐remodeling, senescent‐like state. Other mesenchymal progenitors also can acquire a pro‐inflammatory, adipocyte‐like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro‐inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress‐responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent‐like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro‐inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role.

Subfields: Cardiology and Cardiovascular Medicine, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/2700d5c5dff0c275d60dc0d5c3e617eae35be309

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Citations in the corpus

Aging, Cellular Senescence, and Cancer (2012, background): “Of particular relevance to the role of cellular senescence in aging and age-related disease, many SASP components directly or indirectly promote inflammation (59, 92, 93, 107, 108).”
Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016, neutral): “Age-dependent fat tissue dysfunction is characterized by decreased adipogenesis and adipocyte atrophy 12 .”
LINE-1 derepression in senescent cells triggers interferon and inflammaging (2019, neutral): “Longer term treatments (from 20 to 26 months of age) were effective at opposing several known phenotypes of aging: macrophage infiltration of tissues, a hallmark of chronic inflammation 23,25 , glomerulosclerosis of the kidney 26 and skeletal muscle atrophy 27 (Fig.”
Cellular senescence drives age-dependent hepatic steatosis (2017, neutral): “We therefore do not exclude the possibility that the reduced steatosis we discovered is partially a secondary outcome of clearing senescent cells from other tissues besides the liver, speciﬁcally from adipose tissue where adipocyte senescence might compromise fat storage 43 .”
Fisetin is a senotherapeutic that extends health and lifespan (2018, background): “Senescent cells are rare in young individuals, but increase with age inmultiple tissues, including adipose tissue, skeletal muscle, kidney, and skin of all vertebrates tested [22,23].”
The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs (2015, background): “as senescent cell burden increases in fat tissue with aging and both preadipocytes and endothelial cells contribute to senescent cell burden with aging in fat (Tchkonia et al., 2010).”
Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors (2016, background): “Senescent preadipocytes are potentially important and arguably among the most abundant types of senescent cell in humans (Tchkonia et al., 2010).”
Cellular Senescence: A Translational Perspective (2017, background): “For example, senescent cells accumulate in adipose tissue in diabetes and with age-related metabolic dysfunction (Minamino et al., 2009; Tchkonia et al., 2010; Xu et al., 2015a), osteoarthritic joints (Xu et al.”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “, 2014), chondrocytes (Loeser, 2009), adipocytes (Tchkonia et al., 2010), and osteoclasts (Chung et al.”