Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction
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Abstract
Aging is associated with central fat redistribution and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived stromal cells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25 years) or older women (>60 years). Increased cell passages of young-donor ASCs (in vitro aging) resulted in senescence but not oxidative stress. ASC-derived adipocytes presented impaired adipogenesis but no early mitochondrial dysfunction. Conversely, aged-donor ASCs at early passages displayed oxidative stress and mild senescence. ASC-derived adipocytes exhibited oxidative stress, and early mitochondrial dysfunction but adipogenesis was preserved. In vitro aging of aged-donor ASCs resulted in further increased senescence, mitochondrial dysfunction, oxidative stress, and severe adipocyte dysfunction. When in vitro aged young-donor ASCs were treated with metformin, no alteration was alleviated. Conversely, metformin treatment of aged-donor ASCs decreased oxidative stress and mitochondrial dysfunction resulting in decreased senescence. Metformin’s prevention of oxidative stress and of the resulting senescence improved the cells’ adipogenic capacity and insulin sensitivity. This effect was mediated by the activation of AMP-activated protein kinase as revealed by its specific inhibition and activation. Overall, aging ASC-derived adipocytes presented impaired adipogenesis and insulin sensitivity. Targeting stress-induced senescence of ASCs with metformin may improve age-related adipose tissue dysfunction.
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This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on December 17 2020, follows.
Summary
We feel that the major conclusions are right but the manuscript and story is not quite clear enough at present and there is a lack of deeper cellular and molecular mechanistic understanding of these phenomena to distinguish this work from the previous published studies. That ASC senescence impairs adipogenic differentiation capacity, has been previously reported in eLife in 2015 (doi: 10.7554/eLife.12997). For example, you concluded that adipose derived progenitor cells from older adults have higher potential to become senescence, which impaired adipogenesis. The percentage of senescent cells in adipose tissues is low, but the mechanism of how they could significantly affect adipose tissue functions is …
This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on December 17 2020, follows.
Summary
We feel that the major conclusions are right but the manuscript and story is not quite clear enough at present and there is a lack of deeper cellular and molecular mechanistic understanding of these phenomena to distinguish this work from the previous published studies. That ASC senescence impairs adipogenic differentiation capacity, has been previously reported in eLife in 2015 (doi: 10.7554/eLife.12997). For example, you concluded that adipose derived progenitor cells from older adults have higher potential to become senescence, which impaired adipogenesis. The percentage of senescent cells in adipose tissues is low, but the mechanism of how they could significantly affect adipose tissue functions is unknown. Is this through paracrine effects? or cross talk with other immune cells? etc.
Essential Revisions
Although the authors found that ASC senescence is associated with mitochondrial dysfunction and oxidative stress, it the nature of the links between these cellular events is unclear. It is well-known that mitochondrial dysfunction can directly lead to senescence. If the authors meant to prove that ASC senescence causes early adipocyte mitochondrial dysfunction, more evidence is required.
It has already been reported that ASC senescence impairs adipogenic differentiation capacity, in Elife in 2015 (doi: 10.7554/eLife.12997). Furthermore, although the authors found that metformin prevents the onset of senescence and associated dysfunctions in ASCs, it has been shown in many publications that metformin is a senomorphic drug that can reduce the senescence-associated secretory phenotype. So it is not surprising that metformin can block the effects of senescent ASCs. Also regarding the increased adipogenesis by metformin, it has been reported that metformin can directly regulate adipogenic transcription factors, such as peroxisome proliferator-activated receptor (PPARγ), CCAAT/enhancer binding protein α (C/EBPα). As such, sufficient novelty is lacking at this point, and would require demonstration of causal links among these cellular events.
Several conclusions need to be smoothed out and discussed in more detail. Methods must be described with more details, especially with regard to fat depot digestion (type of collagenase, concentration of collagenase, amount of tissue used for the digestion, are cell yields similar between young and old adipose tissue? Number of plated ASC?). The authors must consider that the term ASC is nowadays related to Adipose stromal cells and not Stem cells. As described in the introduction and method sections, ASC are stromal cells that adhere to plastic including fibroblast, smooth muscle cells, pericytes, endothelial cells, resident macrophages, preadipocytes and progenitors. This must be discussed since distribution and repartition of stromal cells are modulated with aging. The term "adipocyte" must be changed to "differentiated ASC" because adipocytes are characterized by unique lipid droplet (not the case here). The title must be modified. Senescence is related to ASC and not to adipocytes.
Figure 1: It is unclear why the authors conclude about they are recapitulating in vivo aging. If so, one might expect that senescent "young ASC" phenotype may recapitulate the one of "old ASC" with a time lag, what is not the case for all the studied parameters. For example, the % of bgal cells is equivalent between P7 old cells and P11 young cells what is also true for P16, P21 and prelamin A but not for reactive oxygen species or mitochondrial potential. The authors must discuss this point.
Figure 2: Was Cell number at confluency controlled and similar between "young" and "old" ASC? Since post-confluent mitosis are necessary for adipogenesis, one might speculate that the decreased adipogenesis might be related to less cell number and proliferation.
Figure 3 and 4: Cells were treated from P3 with metformin. Do the authors consider potential "resistance" effect? When taking into account the large number of individuals treated with metformin, is there any evidence of an impact of metformin treatment on age-related loss in subcutaneous adipose tissue? Finally, inhibition of senescence may lead to cancer development. The authors must discuss this point.
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