CAAD Theoretical Framework

The currently most widely accepted theory to explain aging is the evolutionary senescence theory of aging (ESTA). The adjacent figure describes the theoretical framework in which metabolism and reactive oxygen species (ROS) play central roles in linking various known elements of ESTA. In contrast to the intrinsic or programmed aging concept, ESTA asserts that natural selection is insensitive to genetic mutations or traits that are operative post-reproduction.

Strikingly, some genes that increase the odds of survival and reproduction early in life may have deleterious effects later on. For instance, the gene p53 – which directs damaged cells to stop reproducing, thus preventing cancer in young populations – may be partly responsible for the aging phenotype by slowing down the renewal of damaged cells in aged populations. This is called antagonistic pleiotropy. In fact, reproduction is the primary goal of the evolutionary imperative. In some cases, the organism even loses its life immediately after accomplishing that goal (e.g. salmon and spiders).

Additionally, reproduction is a metabolically demanding task, especially for those organisms that are likely to die as a result of predation. Hence such organisms need to invest more energy to produce more offspring. This is known as the concept of disposable soma because maintenance of the body is compromised to enhance reproduction. The echo of this concept can be heard in the rate-of-living hypothesis of aging, which is motivated by the finding that, across all forms of life, the rate of metabolism negatively correlates with longevity. Animals with fast metabolic rates tend to age quickly and are vulnerable to degenerative diseases such as cancer. Leakage of ROS appears to be crucial in this paradigm, as ROS cause direct damage to critical cellular components including proteins, membranes, DNA, etc. This deteriorates cellular functions and induces genome instability.

In summary, we believe that high metabolic rate and deficient maintenance translate into disturbed redox homeostasis, elevated oxidative stress, genome instability, shortening of chromosome ends (telomere), diseases and aging.