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Aging Cell. 2019 Mar 25:e12950. doi: 10.1111/acel.12950. [Epub ahead of print]

Targeting senescent cells alleviates obesity-induced metabolic dysfunction.

Author information

1
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
2
Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota.
3
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
4
University of Connecticut Center on Aging, University of Connecticut Health, Farmington, Connecticut.
5
Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
6
Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
7
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
8
Institute for Ageing, Ageing Research Laboratories, Newcastle University, Newcastle upon Tyne, UK.
9
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
10
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
11
Department of Surgery, Mayo Clinic, Rochester, Minnesota.
12
Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
13
Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
14
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
15
Division of Geriatric Medicine and Gerontology, Mayo Clinic, Rochester, Minnesota.
16
Buck Institute for Research on Aging, Novato, California.
17
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
18
Department of Pathology, Mayo Clinic, Rochester, Minnesota.
19
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota.
20
Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota.

Abstract

Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.

KEYWORDS:

adipogenesis; aging; cellular senescence; dasatinib; quercetin; senolytics; type 2 diabetes

PMID:
30907060
DOI:
10.1111/acel.12950
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