Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression

Vliet, Thijmen van; Varela‐Eirin, Marta; Wang, Boshi; Borghesan, Michela; Brandenburg, Simone; Franzin, Rossana; Evangelou, Konstantinos; Seelen, Marc A.; Gorgoulis, Vassilis G.; Demaria, Marco

doi:10.1016/j.molcel.2021.03.018

Cited by 93 publications

(57 citation statements)

References 54 publications

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“…In addition, our finding of increased EPO mRNA levels in the kidney of SGLT-2 inhibitor treated diabetic rats, is consistent with a reduction in P k O 2 and increased HIF expression (not measured). HIF dependent gene expression have been proposed to initiate renal protective mechanisms in the kidney (Chang et al, 2016;van Vliet et al, 2021). These findings are consistent with clinical studies identifying that systemic EPO levels are increased in patients receiving SGLT-2 inhibitors (Mazer et al, 2020;Verma et al, 2019).…”

Section: Discussionsupporting

confidence: 79%

“…These results provide insights into the overwhelming clinical data demonstrating that SGLT-2 inhibitors are renal protective (Neuen et al, 2019;Perkovic et al, 2019). The small decrease in renal microvascular P k O 2 may represent a condition of "physiologic hypoxia" which we speculate may activate an AMP kinase dependent mechanism to protect renal cells via inhibition of cellular senescence (van Vliet et al, 2021). Thus, with dapagliflozin treatment of diabetic rats, F I G U R E 3 Assessment of the impact of dapagliflozin (DAPA) treatment on real-time renal microvascular P k O 2 at different levels of inspired oxygen (F I O 2 ) in non-diabetic control or diabetic rats (protocol #1).…”

Section: Discussionmentioning

confidence: 74%

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Impact of sodium glucose linked cotransporter‐2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus

et al. 2021

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 74%

Impact of sodium glucose linked cotransporter‐2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus

et al. 2021

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“…Furthermore, lower O 2 levels are required for a human-like SASP in cultured murine fibroblasts 67 , and this SASP is closer to that observed with age. Despite these findings, sub-physiological levels of oxygen (that is, hypoxia) can also activate AMPK, which can suppress the SASP by mTOR inhibition 68 . More broadly, these data signal the potential for artifacts when studying senescence (and likely many other conditions) using atmospheric rather than physiological oxygen levels.…”

Section: Metabolic Drivers Of Senescencementioning

confidence: 99%

The metabolic roots of senescence: mechanisms and opportunities for intervention

2021

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Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.

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“…Exercise also decreases the partial pressure of oxygen in skeletal muscle and activates HIF-1α ( Ameln et al, 2005 ). Thus, exercise has the potential to regulate various signaling pathways, some of which are involved in the control of cellular senescence ( Wang et al, 2003 ; Jones et al, 2005 ; Welford and Giaccia, 2011 ; Davalli et al, 2016 ; Zhang et al, 2016 ; Nacarelli et al, 2019 ; Chan et al, 2020 ; Vliet et al, 2021 ) ( Figure 3 ). Accordingly, senescence-targeted exercise therapy has enormous potential for clinical benefit.…”

Section: Potential Of Senotherapy For Muscle Inflammation and Regenerationmentioning

confidence: 99%

Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

Saito

Chikenji

2021

Front. Pharmacol.

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Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat age-related disease, from the standpoint of improving muscle regeneration.

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Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression

Cited by 93 publications

References 54 publications

Impact of sodium glucose linked cotransporter‐2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus

Impact of sodium glucose linked cotransporter‐2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus

The metabolic roots of senescence: mechanisms and opportunities for intervention

Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

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