Yesterday we discussed mitochondrial sequence changes over evolutionary time and their possible connection to the evolution of lifespan. Today, we consider a much smaller timescale: mitochondrial sequence changes in somatic tissue over the lifespan of a single organism, and their possible role in age-related decline. In Cancer Research, Kujoth et al. review the issue:

Mutations in mitochondrial DNA (mtDNA) accumulate during aging, but their significance to longevity and age-associated disease has been uncertain. Recently, in support of the hypothesis that mtDNA integrity is important, we have shown that age-associated diseases arise more rapidly in mice where mtDNA mutations and increased levels of apoptosis occur at higher rates than normal due to expression of an error-prone mtDNA polymerase. Further studies in this model may provide deeper insights into the relationship between mitochondria, aging, and susceptibility to age-associated diseases, such as cancer.

The review focuses on a specific system: mice expressing an exonuclease-deficient allele of the mtDNA polymerase gamma; these animals accumulate mitochondrial mutations much more rapidly than wildtype. They are unquestionably unwell and could quite reasonably be called progeroid: they exhibit “reduced life span, hair graying and alopecia, cardiac enlargement with functional alterations, muscle loss, reduced fertility, accelerated thymic involution, kyphosis, and decreased bone density, and age-related hearing loss (presbycusis).”

In addition to rapid mitochondrial mutation, the mice also exhibit a high rate of apoptosis in a variety of tissues. The authors (who, along with workers in other labs, have extensively studied the pol-gamma mutants) favor a model in which mtDNA mutations are the primary phenotype, apoptosis secondary, and accelerated aging the ultimate result:

  1. Mutations generate low-functioning proteins, which interfere with oxidative phosphorylation.

  2. Defective ox/phos in turn triggers apoptosis, presumably of the mitochondria-mediated flavor. (One gene required for mitochondria-mediated apoptosis is p66shc, which generates ROS upon receiving electrons from cytochrome c. Intriguingly in this context, the p66shc -/- mutant lives 30% longer than wild type.)
  3. High rates of apoptosis destroy irreplaceable cells, and tissue function is compromised, mimicking age-related decline.

In this view, the loss of cells is the primary cause of tissue aging. This stands in contrast to the model emerging in the cellular senescence field, where we’re coming to believe that tissues are compromised by malfunctioning senescent cells that persist for long periods, damaging their microenvironments for the remainder of their twisted lives.

The models don’t compete ā€” an organism could simultaneously lose worthwhile cells and accumulate nefarious ones, and suffer in different ways from both ā€” but the relative importance of these processes remains to be evaluated.