The biology of aging

3. Cellular mechanisms of aging

Fifty years ago, Harman postulated a theory in which he considered free radicals formation the main cause of aging5. His hypothesis is based on the observation that oxygen molecules, that are essential for life, can be modified to produce extremely toxic derivatives, almost incompatible with life itself. In fact, molecular oxygen can generate reactive metabolites, causing profound oxidative damages to biological macromolecules. Mitochondrial and genomic DNA can be altered in their chemical composition, they can be subjected to breaks in the double helix structure and recruit cellular proteins in an abnormal and uncontrolled way. Membrane lipids become modified by reactive oxygen metabolites (peroxidation) and cellular proteins are inactivated and/or rapidly degraded6.
There are several experimental evidences to support this theory:
1. the number of oxidized molecules increases with age;
2. the artificial introduction of additional anti-oxidant enzymes in experimental animals prolongs life;
3. differences in longevity among various organisms within a given species can be correlated with the amount of oxidative stress.
To eliminate toxic reactive oxygen species, cells can synthesize protective proteins like Super-Oxide-Dismutases (SOD) and Peroxidases.
Furthermore, the decrease of the assumption of calories in the diet causes a diminished oxidative stress with a delay in the formation of pathogenic cellular modifications associated with aging and a progressive elongation of life span (see later)6.
In vitro cultures of senescent cells proved to be a very useful model system to study the aging process at the cellular level7. Following a number of cell divisions, senescent cells permanently exit the cell cycle. This phenomenon is highlighted by profound morphological and biochemical changes that underline the existence of a specific genetic program. The life span of primary cells in culture in considerably increased by adding anti-oxidant molecules or by decreasing oxygen concentration in the external environment.
Several cellular organelles show a prominent role in this phenomenon, as demonstrated both in vitro and in vivo (Fig. 1):
1. Mitochondria: the vast majority of reactive oxygen species is generated within the mitochondria, where cellular energy is produced. The integrity of mitochondria diminishes with age. In senescent cells, mitochondria display an altered morphology, produce elevated levels of toxic oxygen metabolites and reduced levels of energy. Mitochondrial DNA accumulates mutations and aberrant chemical modifications6.
2. Telomeres: they represent the terminal portion of a chromosome and are formed by six-bases long repeats. During each cell division, telomere length decreases substantially (in the range of 50-200 bases/ division). The enzyme Telomerase can synthesize new repeats, counterbalancing those lost during cell division. When the loss of telomeres reaches a certain threshold, cells become senescent and enter apoptosis. Oxidative stress increases the rate of telomeres loss7.
3. Protein Degradation: with aging, cells tend to accumulate damaged proteins. Senescent cells have a reduced proteasome activity (a multi-protein complex responsible for protein degradation).

Figure 1: Structure of a cell

During the aging process, organisms exhibit increased damages and decreased defense mechanisms, with an overall diminished threshold for activation of programmed cell death. Nonetheless, the level of cell death that is required to have an altered and non-functional tissue still needs to be established.
The most reasonable model postulates that mutations and damages accumulate during aging until the threshold level is reached and cellular homeostatic balance collapses. Different cell types have diverse combinations of somatic mutations, accumulation of toxic metabolites and mitochondrial damages. In this context, an organism needs to make a choice on how to use its metabolic energy, how much to invest in damage repair and how to dispose of vulnerable and damaged cells. Recently, it has been demonstrated that organisms with a prolonged life span employ a higher level of energy in DNA repair.

5 Harman D. (1956): “Aging: a theory based on free radical and radiation chemistry”, J. Gerontol, no. 11, pp. 298-300.
6 Balaban, R.S., Nemoto, S. and Finkel, T. (2005): “Mitochondria, oxidant and aging”, Cell, no. 25, 120(4), pp. 483-95.
7 Kim, S., Kaminker, P. and Campisi, J. (2002): “Telomeres, aging and cancer: in search of a happy ending”, Oncogene, no. 21, pp. 5003-511.

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