Rapamycin decelerates cellular senescence

Abstract

When the cell cycle is arrested but cellular growth is not, then cells senesce, permanently losing proliferative potential. Here we demonstrated that the duration of cell cycle arrest determines a progressive loss of proliferative capacity. In human and rodent cell lines, rapamycin (an inhibitor of mTOR) dramatically decelerated loss of proliferative potential caused by ectopic p21, p16 and sodium butyrate-induced p21. Thus, when the cell cycle was arrested by these factors in the presence of rapamycin, cells retained the capacity to resume proliferation, once p21, p16 or sodium butyrate were removed. While rapamycin prevented the permanent loss of proliferative potential in arrested cells, it did not force the arrested cells into proliferation. During cell cycle arrest, rapamycin transformed the irreversible arrest into a reversible condition. Our data demonstrate that senescence can be pharmacologically suppressed.

p62/SQSTM1 at the interface of aging, autophagy, and disease

“…In fact, Snell/Dwarf mice-derived fibroblasts show lower levels of mTORC1 activity and enhanced autophagy in response to stress (Wang and Miller 2012). Similarly, we and others show that prolonged reduction of mTORC1 signaling increases autophagy and delays cellular senescence (Demidenko et al 2009;Lerner et al 2013;Cao et al 2011). Since the expression of p62/SQSTM1 is critical to prevent so many age-related processes and is necessary for the beneficial effects of rapamycin on human cells, it is possible that the pro-longevity effects of reducing IGF-1/mTORC1 signaling are due, at least in part, to altered p62/SQSTM1 dynamics.…”

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

“…Our study confirmed that rapamycin can prevent the induction of cell senescence by either genotoxic agents or by replicative exhaustion (Demidenko et al ., 2009; Cao et al ., 2011; Lerner et al ., 2013). In addition, by identifying the role played by the Nrf2 pathway on these effects, we identify that the inhibition of cellular senescence by rapamycin can be molecularly dissected into effects on cell cycle arrest, and secretion of pro‐inflammatory molecules (SASP) and induction of senescence‐associated β‐galactosidase (β‐gal).…”

“…Earlier studies using rapamycin as an inhibitor of cellular senescence focused on the effect on cell cycle arrest and β‐gal staining, where the decreased in 16/p21 were one of the parameters measured by several laboratories (Demidenko et al ., 2009; Lerner et al ., 2013, etc.). The interesting data shown by Campisi's and Gil's laboratories last year simply changed our vision about cellular senescence, as a disconnection was identified between these two arms, cell cycle arrest and β‐gal/SASP.…”

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

“…Increased expression of p53 in differentiated stem cells may be indicative of an increase in cellular senescence and therefore to their reduced functionality. However, it has also been shown that cellular senescence, as defined by the loss of proliferative potential, is linked to cellular over-activation and correlates with cellular hypertrophy [59]. In the case of differentiated stem cells, this over activation might correlate with the increase in growth factor secretion and consequently the increased stimulation of neurite outgrowth.…”