As cells age, detritus inevitably accumulates; one theory of aging holds that rising levels of unwanted molecules will eventually become cytotoxic — the so-called “garbage catastrophe” model — and this, in turn, could cause age-related decline in cell and tissue function.

Cells have a variety of means to eliminate misfolded, damaged and covalently altered proteins, among them the ubiquitin-proteasome pathway and the various flavors of autophagy. These mechanisms of cellular trash collection have come under increasing scrutiny by biogerontologists — and the results, while generally consistent with the idea that protein recycling is important in the aging process, can often be surprising: in some organ systems (like the brain) excessive autophagy can be deleterious. And in prematurely aging mice, the most recent observations are somewhat counter-intuitive:

Activation of autophagy in progeria: Autophagy and aging: New lessons from progeroid mice, Mariño y López-Otín:

We have recently reported the unexpected finding that distinct progeroid murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. … [T]he observed autophagic increase is associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong lifespan.

Regulation by circadian clocks: Diurnal rhythms of autophagy: Implications for cell biology and human disease, Sachdeva and Thompson:

As a consequence of the induction of autophagy during short periods of fasting, animals experience diurnal rhythms of autophagy in concert with their circadian cycle. … Whether the circadian clock directly regulates autophagy in mammalian cells, or whether autophagy may play a role in the cycling of mammalian cell clocks is not yet clear. Nevertheless, the relationship between circadian cycles and autophagy is an intriguing area for future study and has implications for multiple human diseases, including aging, neurodegeneration, and cancer.

Life extension therapeutics?: Proteasome activation as a novel antiaging strategy, Chondrogianni and Gonos:

As proteasome has an impaired function during aging, emphasis has been given recently in identifying ways of its activation. A number of studies have shown that the proteasome can be activated by genetic manipulations as well as by factors that affect its conformation and stability. Importantly the developed proteasome activated cell lines exhibit an extended lifespan. … Finally as few natural compounds have been identified having proteasome activation properties, we discuss the advantages of this novel antiaging strategy.

Protein misfolding in neuropathological states: Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging, Rick Morimoto:

Adaptation and survival requires the ability to sense damaged proteins and to coordinate the activities of protective stress response pathways and chaperone networks. Yet, despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress when conformationally challenged aggregation-prone proteins are expressed in cancer, metabolic disease, and neurodegenerative disease. The decline in biosynthetic and repair activities that compromises the integrity of the proteome is influenced strongly by genes that control aging, thus linking stress and protein homeostasis with the health and life span of the organism.

Looks like tomorrow will be a big one on mitochondria and oxidative damage.