Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice

Abstract

The TOR (Target of Rapamycin) pathway accelerates cellular and organismal aging. Similar to rapamycin, p53 can inhibit the mTOR pathway in some mammalian cells. Mice lacking one copy of p53 (p53+/− mice) have an increased cancer incidence and a shorter lifespan. We hypothesize that rapamycin can delay cancer in heterozygous p53+/− mice. Here we show that rapamycin (given in a drinking water) extended the mean lifespan of p53+/− mice by 10% and when treatment started early in life (at the age less than 5 months) by 28%. In addition, rapamycin decreased the incidence of spontaneous tumors. This observation may have applications in management of Li-Fraumeni syndrome patients characterized by heterozygous mutations in the p53 gene.

Dysregulation of the mTOR pathway in p53-deficient mice

“…87 Similarly, rapamycin delayed cancer in p53 +/− and p53 −/− mice. 63,64 Noteworthy, the effect of rapamycin was blunted when it was used later in life, consistent with its indirect anti-cancer effect. 63 In conclusion, mice lacking p53 is characterized by oncophilic metabolism, an additional factor fostering carcinogenesis.…”

“…[60][61][62] Rapamycin extends lifespan and delays cancer in p53 +/− and p53 −/− mice. [63][64][65] In p53 −/− mice both direct (anti-cancer) and indirect (anti-aging) models identically predict that rapamycin will delay cancer and extend life span. There is a hint for indirect effects: rapamycin is more effective when given early in life.…”

“…There is a hint for indirect effects: rapamycin is more effective when given early in life. 63 (In contrast, classic anti-cancer agents such as radiation promote cancer, especially when given early in life.) Do p53 −/− mice have metabolic and tissue alterations that may favor both aging and cancer?…”

Molecular dynamics of the full-length p53 monomer

“…56,57 The regulation of cell death by the p53 protein is quite complex, acting both at the level of autophagy, 58 lysosomes, 59 or at the core machinery of programmed cell death. [60][61][62][63][64][65] In addition to DNA damage response and cell death, p53 plays a crucial role in regulating cellular senescence [66][67][68] by interacting, for example, with MageA2, 69 PATZ1, 70 4E-BP1, 71 mTOR, 72,73 highlighting the vast complexity of this crucial regulation.…”

Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Furthermore, rapamycin delays the onset of cancer in mice. [3][4][5][6][7][9][10][11][12][13]15,18 Rapamycin and everolimus (a rapamycin analog) decrease the risk of cancer in humans, who receive these rapalogs to prevent transplant rejection. 1,[21][22][23][24] Therefore, rapalogs such as rapamycin are considered for both prevention of cancer and extension of healthy life span in humans.…”