Rapamycin improves healthspan but not inflammaging in nfκb1^−/− mice

Abstract

Increased activation of the major pro‐inflammatory NF‐κB pathway leads to numerous age‐related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF‐κB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF‐κB signalling, such as that which occurs in several age‐related chronic diseases. In this study, we investigated whether rapamycin could ameliorate age‐associated phenotypes in a mouse model of genetically enhanced NF‐κB activity (nfκb1 −/−) characterized by low‐grade chronic inflammation, accelerated aging and CLD. We found that, despite showing no beneficial effects in lifespan and inflammaging, rapamycin reduced frailty and improved long‐term memory, neuromuscular coordination and tissue architecture. Importantly, markers of cellular senescence, a known driver of age‐related pathology, were alleviated in rapamycin‐fed animals. Our results indicate that, in conditions of genetically enhanced NF‐κB, rapamycin delays aging phenotypes and improves healthspan uncoupled from its role as a suppressor of inflammation.

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction

“…It is known that oxidative stress is an important contributor to activation of a DDR, with telomeres being particularly sensitive to imbalances in ROS homeostasis (Kruk et al , ; Petersen et al , ; Rochette & Brash, ). In fact, mitochondria are a major source of ROS generation and have been implicated as key components for the generation and replenishment of DNA damage foci, an important effector of senescence (Passos et al , ; Correia‐Melo et al , , ). Moreover, stimulation of the CXCR3 receptor has been shown to increase oxidative stress in human kidney cells (Bek et al , ).…”

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

“…It has been shown in non-tumoral vas deferens epithelial cells (VDEC) or PC3 cells, when stably expressing AR, that phospho-Akt at serine 473 is increased in less than an hour upon androgen stimulation [133]. Additionally, the role of the mTORC1 in driving SASP has been widely established [134]. Furthermore, mTORC1 can be targeted to eliminate senescent cells [134].…”

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

“…These mice lack p105 and p50 expression, which leads to the over activation of the FB pathway and induction of chronic low-grade inflammation. Interestingly, rapamycin treatment prevents age-related frailty without altering inflammation by decreasing the number of senescence cells [189].…”

“…Autophagy-mitochondria mTOR inhibition Fly, mouse, worm [30,172,179] TNF-α expression blockade Monocytes [182,183] NK cell inhibition NK cells [184] PD1 + T cell blockade and memory CD8 + T cell increase T cells [186,187] SASP blockade and senescent cell elimination Senescent cells [188,189] Microglia activation inhibition Mouse brain [192][193][194][195]197] Immune cell infiltration blockade γδ T cells, granulocytes [197,198] Regulatory T cell polarization Brain T cells [197,198] Rapamycin Inflammation…”