Macromolecular deterioration as the ultimate constraint on human lifespan

A number of tissues and organs in the human body contain abundant proteins that are long-lived. This includes the heart, lung, brain, bone and connective tissues. It is proposed that the accumulation of modifications to such long-lived proteins over a period of decades alters the properties of the organs and tissues in which they reside. Such insidious processes may affect human health, fitness and ultimately may limit our lifespan. The human lens, which contains proteins that do not turnover, is used to illustrate the impact of these gradual deleterious modifications. On the basis of data derived from the lens, it is postulated that the intrinsic instability of certain amino acid residues, which leads to truncation, racemisation and deamidation, is primarily responsible for the age-related deterioration of such proteins. Since these post-translational modifications accumulate over a period of many years, they can only be studied using organisms that have lifespans measured in decades. One conclusion is that there may be important aspects of human aging that can be studied only using long-lived animals.