Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition

Cell Cycle. 2006 Sep;5(18):2087-102. doi: 10.4161/cc.5.18.3288. Epub 2006 Sep 15.

Abstract

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases. Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.

Publication types

  • Review

MeSH terms

  • Aging / drug effects
  • Aging / physiology*
  • Animals
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cellular Senescence / drug effects
  • Cellular Senescence / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use
  • Longevity / drug effects
  • Longevity / physiology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Kinases
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sirolimus / pharmacology*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases

Substances

  • Drosophila Proteins
  • Immunosuppressive Agents
  • Protein Kinases
  • target of rapamycin protein, Drosophila
  • TOR Serine-Threonine Kinases
  • Sirolimus