Age-dependent changes of macromolecules

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Age-dependent changes of macromolecules

Among the oldest hypotheses regarding the causes of aging is macromolecular damage. There are myriad types of macromolecular damage. This knowledge poses a major challenge: identifying which types of damage are most important for which tissues, identifying the sources of each type of damage, and determining whether damage can be prevented or reversed. Now, there is also a new perspective in understanding the relationship between damage and aging: cellular responses to damage may be doubleedged swords. In the short term, these responses protect cells, tissues, and organisms from damage sequela. Over time, however, cellular responses may compromise the integrity and function of tissues and organs and contribute to aging. The most vulnerable targets were thought to be long-lived molecules, such as extracellular matrix proteins, or template molecules, such as DNA. The sources of damage are broad, ranging from the high fluxes of UV radiation to which the first replicating organisms were exposed to mitochondrial ROS. Mitochondrial ROS are still considered a major cause of aging, despite data suggesting that not all age-related phenotypes or diseases are caused by ROS.

Damage can interfere with molecular function and hence important cellular processes (e.g., transcription, translation, metabolism). Alternatively, damaged molecules can accumulate and nonspecifi cally impair cellular function (e.g., in the case of protein aggregates). Macromolecular damage can also drive aging indirectly. Examples include DNA mutations, caused by the replication of damaged templates or imperfect repair, and cellular death or senescence (irreversible cell cycle arrest), which occur when damage loads are overwhelmingly high.

Most animal models with accelerated damage accumulation show multiple signs of premature aging and a shortened life span. For example, mice deficient in single antioxidant defense genes do not, in general, age prematurely, although some are cancer prone. On the other hand, many mice with engineered defects in DNA repair genes display multiple symptoms of premature aging that are indistinguishable from those displayed by aged wild-type littermates. These findings support the idea that the DNA damage, or its sequela, can cause aging.