Molecular Mechanisms of Aging

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The Real Fountain of Youth: Modern conceptions of ageing and proposed methods of lifespan extension.

Mitchell S. Kirby
121 Little Hall
Princeton University
Princeton, NJ 08544

Advisor: Dr. Leon Rosenberg

May 4th, 2010

This paper represents my own work in accordance with University regulations.

Abstract
The mechanisms that regulate cellular senescence, organismal ageing, and species-specific lifespan depend on a synergy of pathways that are multifactorial and extremely complex, though not yet completely understood. Recently, the development of new molecular techniques has elucidated, at least in part, the primary pathways involved in ageing. In parallel with the search to uncover the factors that control ageing is the endeavor to discover methods of extending lifespan, in hopes of living both youthfully and longer. Specifically, caloric restriction regimens and rapamycin feeding have been shown to increase lifespan in a variety of species, though other methods will be discussed as well. The illumination of ageing mechanisms side-by-side with means of extending lifespan provides a foundation from which to determine a complete multidimensional map of ageing pathways and the place of various lifespan extension methods within it. Furthermore, this information acts as a stepping stone from which to evaluate the feasibility of potential lifespan extenders and to grant recommendations for a dietary regimen bestowing a long and healthy life to its patrons. Specific Aims

The Fountain of Youth, a mystical spring that bestows youth and immortality to those who drink from it, captured the attention of Spanish Conquistadors exploring the American terrain. Though many centuries have passed, the fascination with delaying ageing and living forever has never dwindled. Today, scientists serve as contemporary conquistadors, searching for the real Fountain of Youth in the form of pharmaceuticals and health regimens that will increase lifespan, delay ageing, and decrease the onset of age-associated diseases. Before successful lifespan extension models can be implemented in humans, the following questions must be answered (Sander et al., 2008): What are the signs of human ageing? Is there a limit to the length of human life? Why does ageing occur? What are the genetic factors involved in ageing? To what extent do environmental factors influence ageing? The current study seeks to address these questions by analyzing the various theories of ageing, and relating them to each other and to means of lifespan extension. Once the current understanding of the molecular basis of ageing is established, it will be used to assess the feasibility of methodologies thought to delay death and to suggest eating habits associated with increased lifespan and healthspan. Background and Significance

What is Ageing?
Before attempting to uncover the mechanisms that guide the process of ageing, it is essential to understand what ageing actually is. Most generally, ageing is the accumulation of changes in an organism that over time leads to an increase in stress vulnerability and to a decrease in physiological homeostasis (Bowen and Atwood, 2004; Sander et al, 2008). Though the concept of age is commonly regarded as the time an organism has been alive, some believe a better functional measure is a determination of the amount of time an organism has until its death (Birren and Cunningham, 1985).

Ageing on an organismal scale is the result of the accumulation of senescence on a cellular level. Replicative senescence, or the loss of the cellular ability to divide, was first described by Dr. Leonard Hayflick upon discovering that human fibroblasts can undergo only a finite number of cell divisions (Hayflick and Moorehead, 1961). Interestingly, as the cells approached their replicative limit, their cellular structure deteriorated, they failed to produce enzymes or energy, and they accumulated a great deal of waste, all features...
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