Scientists in several recent studies suggested, that apoptosis might limit mammalian life span.
Mice with a targeted disruption in the p66shc gene exhibited a longer life span than wild-type animals.
Importantly, cells derived from the p66shc mice were resistant to DNA damage-induced apoptosis in culture.
Further, p66shc is one of the down-stream targets of the key regulator of damage-induced apoptosis, the tumour suppressor p53.
In the cell culture studies, p66shc cells were resistant to oxidative stress or ionizing radiation, which both kill cells by the p53-dependent cell death pathway.
This finding suggested that apoptosis might be a two-edged sword, providing critical tumour surveillance during the reproductive years, but contributing to organ dysfunction and aging in a post reproductive period.
A second finding may also implicate apoptosis in mammalian aging.
The yeast SIR2 gene appeared to promote survival in a wide range of organisms.
In yeast, this gene promoted long life span in mother cells, and was crucial to the generation of the long-surviving, specialized cell type termed spores.
In C. elegans, an organism that diverged from the yeast lineage a billion years ago, the SIR2 ortholog sir-2.1 also promoted long life in adult animals and regulated the formation of dauers during development.
Recently, it has been shown that a cytoplasmic Sir2p homolog can promote survival in the protozoan parasite Leishmania by preventing apoptosis.
The mammalian ortholog of SIR2, SIRT1, repressed the activity of p53 and therefore down-regulated apoptosis.
If the survival function of SIR2 genes observed in yeast, worms, and protozoans extended to mammals, apoptosis may thus was important in limiting mammalian life span.
Furthermore, a hyperactive allele of p53 was described that confers enhanced tumor surveillance on transgenic mice.
Interestingly, these mice developed early organ degeneration and signs of premature aging.
These phenotypes further supported the idea that apoptosis may limit mammalian life span, because its enhancement apparently speeds up the aging process.
The above studies raised the possibility that any process extending mammalian life span would have to slow down apoptosis.
However, in some organs with rapidly dividing cells, apoptosis actually increased during CR, for example, in the liver and the gut.
This increased along with the known shrinkage of cells during CR, may both contributes to the downsizing of these organs in the restricted animal.
The increased rate of apoptosis may minimize the risk of cancer during CR.
The increase in apoptosis in these organs appeared at odds with any central role for SIR2.
However, it was possible that neuroendocrine changes were dominant in up-regulating apoptosis in this subset of organs.
The brain is the one organ that does not shrink during CR.
Is it possible that the link between apoptosis and life span, discussed above, is due to effects on neurons?
Could p66shc KO mice live longer because neuronal death is slowed?
It would be of interest to determine whether CR slows cell death of neurons.
This may be difficult to visualize in animals, because apoptosis is transient and the number of apoptotic cells at any given time will be low.
However, it may be possible to test whether interventions that slow aging, such as CR, result in less apoptosis when neuronal cells are harvested and cultured.