Relationship between Replicative and Chronological Aging

Cells that have been maintained in stationary phase for a sufficient length of time (chronologically aged) demonstrate reduced replicative capacity (Ashrafi et al., 1999), suggesting that chronological and replicative aging are linked in some way. This link appears to be unrelated to ERCs, as chronologically aged cells do not have a detectable increase in ERC levels relative to young cells (Ashrafi et al., 1999). One attractive hypothesis is that accumulation of oxidatively damaged proteins during chronological aging might contribute to premature replicative senescence. It has been reported that oxida-tively damaged proteins accumulate with replicative age (Reverter-Branchat et al., 2004); however, thus far, no direct link between oxidative damage and replicative capacity in yeast has been demonstrated. In fact, deletion of SOD2, which results in sensitivity to oxidative stress and dramatically shortens chronological life span, has no effect on replicative life span (Kaeberlein et al., 2005a). Thus, it seems unlikely that oxidative damage limits replicative capacity, at least under normal conditions. It may be the case, however, that in chronologically aged cells, an abnormally high level of oxidative damage is sufficient to detrimentally affect replicative capacity.

Another link between replicative and chronological aging is seen in the response of cells to CR. The same nutrient sensing pathways play an important role in determining the rate at which cells age both chronologically and replicatively, as evidenced by the fact that decreased activity of PKA or Sch9 increases both chronological and replicative life span (see Conserved Nutrient Sensing Pathways as a Mediator of CR in Yeast and Nutrient Sensing and Chronological Aging). Intriguingly, the molecular mechanisms by which nutrient depletion slows aging appear to be quite different in dividing and nondividing yeast cells.

The mechanistic divergence for replicative versus chronological life-span extension by CR is of particular interest in light of the fact that CR slows aging in both

REPLICATIVE CHRONOLOGICAL

AGING AGING

Figure 18.3. Nutrient responsive pathways that promote aging in yeast. PKA, SCH9, and TOR activate overlapping downstream targets in response to environmental nutrients and limit both replicative and chronological life span. The downstream effectors, although unidentified at present, appear to be different for replicative and chronological aging.

mitotic and postmitotic cells of multicellular organisms. The yeast model provides a molecular explanation for how such a system might have evolved from a unicellular progenitor. TOR, Sch9, and PKA are known to converge on a shared set of downstream targets that impact a variety of cellular processes, including regulation of cell size, metabolic flux through many of the major biosyn-thetic and degradative pathways, ribosome biosynthesis and translation, and stress response (Figure 18.3).

Through modulation of specific subsets of these downstream targets, it is possible to imagine how aging can be regulated in both dividing and nondividing cells in response to similar environmental parameters, such as nutrient availability.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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