Friday, October 09, 2009

NEJM Review on Aging and Cancer

The latest issue of the New England Journal of Medicine has this interesting review article on aging and cancer. Here is a sample:

DNA damage has emerged as a major culprit in cancer and many diseases related to aging. The stability of the genome is supported by an intricate machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. In addition, DNA damage and other stresses can trigger a highly conserved, anticancer, antiaging survival response that suppresses metabolism and growth and boosts defenses that maintain the integrity of the cell. Induction of the survival response may allow interventions that improve health and extend the life span. Recently, the first candidate for such interventions, rapamycin (also known as sirolimus), has been identified.1 Compromised repair systems in tumors also offer opportunities for intervention, making it possible to attack malignant cells in which maintenance of the genome has been weakened.

Time-dependent accumulation of damage in cells and organs is associated with gradual functional decline and aging.2 The molecular basis of this phenomenon is unclear,3,4,5 whereas in cancer, DNA alterations are the major culprit. In this review, I present evidence that cancer and diseases of aging are two sides of the DNA-damage problem. An examination of the importance of DNA damage and the systems of genome maintenance in relation to aging is followed by an account of the derailment of genome guardian mechanisms in cancer and of how this cancer-specific phenomenon can be exploited for treatment.

....DNA damage can trigger the development of cancer, accelerate aging, or both, depending on the type, amount, and location of the damage; the type of cell sustaining the damage and its stage in the cell cycle; and the specific repair, checkpoint, and effector systems involved. When the damage is not repaired, the outcome may be cancer or, if cell death or senescence occurs, protection from cancer, but the trade-off is acceleration of the aging process. The development of cancer and the process of aging can be delayed by reducing the load of DNA damage — by avoiding or limiting exposure to exogenous genotoxins and by suppressing metabolism — thereby producing fewer reactive species. However, DNA damage, like caloric restriction, can also elicit a protective survival response that promotes longevity and healthy aging. Recently, the use of sirolimus in mice was found to extend their life span and delay the development of conditions associated with aging, including cancer.1 Sirolimus is one of presumably many compounds that may elicit the survival response. The frequent derailment of DNA damage-response systems in tumors presents another possible route by which new treatments can act selectively on the tumor.