The biology of aging

1. Introduction

Gerontology and biology consider the process of aging a continuous, universal, progressive, intrinsic and deleterious phenomenon that can progressively reduce the capability of a certain organism to maintain its homeostasis within a given environment, increasing the risk of illness or death.
In this article, we will examine the most recent theories on the biological mechanisms of aging. We will analyze the biochemical and physiological characteristics of aged organisms and senescent cells cultured in vitro. Furthermore, we will focus on the implications of data obtained from genetic experiments, in which modified longevity is achieved in animal model systems. We will then describe some examples of human genetic disorders, in which patients show signs of premature aging. In the end, we will discuss the possible implications of these most recent discoveries for the development of anti-aging drugs.
2. Various theories of aging

A question a biologist might ask is whether the aging process might lead to a clear advantage during natural selection and evolution. The progressive loss of cerebral and physiological functions, the increased vulnerability to environmental toxins, the higher rate of pathologies and the decline of fertility are specific features of the aging process that are difficult to reconcile with a specific advantage during evolution. Why isn’t aging completely blocked by natural selection? A reasonable answer to this question suggests that aging and death prevent the accumulation of a great number of living organisms that would be incompatible with existing resources. Nonetheless, this model is based on a risky anthropomorphic view of the problem: wild animals rarely survive till aging. Most usually, wild organisms succumb at a rather young age due to extrinsic causes, such as accidents or incidents with not exactly ‘friendly’ predators. Therefore, aging is not essential for survival, and thus is not subjected to selective pressure1. In this context, the nobel prize Medawar hypothesized, in his Mutation Accumulation Theory, that only those organisms that survive ‘extrinsic’ causes of death can display the effects of genetic mutations accumulated in their germlines2. Thus, only germlines are subjected to a very limited natural selection.
As a consequence, the longevity within a certain species is probably optimized as a function of its ecological niche and its ‘extrinsic’ mortality. Evolutionary adaptations, such as the ability to fly or the development of an enlarged and more complex brain, can reduce ‘extrinsic’ mortality and therefore are associated with an increased longevity.
Biologists wonder whether a genetic program for aging exists. The presence of such genetic program should not come as a surprise. In nature there are fundamental and well characterized metabolic pathways that, under specific signals from the outside (external environment) or from the inside (surrounding cellular tissues), can cause programmed and physiological cell death (apoptosis) of million of cells. Nevertheless, no combination of known genetic mutations has been able, so far, to generate an immortal animal or human being, even though some genetic alterations can modify longevity in laboratory animal models.
An intriguing theory, the Disposable Soma Theory, starts from the observation that complex living organisms need to optimize the consumption and usage of available metabolic sources3,4. The amount of metabolic energy is, in fact, limited and requires a specific program of disposal and usage. In a very simplified classification of the possible types of energy disposal, we can identify two categories of energy-dependent activities:
1. maintenance of cellular physiological conditions, through continuous repair of macromolecular components within cells and tissues;
2. survival in a given environment and reproduction.
The molecular and metabolic mechanisms for cellular homeostasis require a large amount of energy. Nevertheless, 90% of wild animals succumb during the first year of life both for the inability to preserve a proper body temperature and for the encounter with predators. Thus, every organism needs a compromise: during the first phases of life it is mandatory to fight against external hostile conditions and to reproduce. Consequently, this choice implies the use of a minimal amount of energy for the maintenance of the cellular systems in order to keep them compatible with life. The small quantity of energy consumed inevitably causes an accumulation of cellular damages that has no consequences on the initial survival but participates in the aging process.
Based on this theory, it is possible to predict some biological mechanisms of aging:
1. aging results from an accumulation of cellular and molecular damages of various sources that cannot be repaired;
2. longevity is mainly controlled by regulatory genes of cellular and molecular repair;
3. the expression of those genes and, thus, the usage of metabolic energy can be regulated;
4. the germline, which is immortal, displays the highest level of repair and survival;
5. the mechanisms of aging are stochastic.

Giovanni Armenise-Harvard Foundation Laboratory, Department of Neurobiology, International School for Advanced Studies (I.S.A.S./S.I.S.S.A.). Address: AREA Science Park – Basovizza, 34012 – Trieste, Italy.
1 Kirkwood, T.B.L. (2005): “Understanding the odd science of aging”. Cell, no. 25, 120 (4), pp. 437-47.
2 Medawar, P.B. (1952): An unsolved problem of biology, Lewis, London.
3 Kirkwood, T.B.L. (1977): “Evolution of ageing”, Nature, 27, pp. 301-304.
4 Kirkwood, T.B.L. (2005): “Understanding the odd science of aging”, Cell, no. 25, 120 (4), pp. 437-47.

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