R. Arking, C.N. Giroux

The genetic analysis of aging has dramatically improved our understanding of the aging process by highlighting the role of longevity determinant mechanisms (e.g., the insulin-like signaling pathway). But there are important remaining difficulties. We need to explain how the aging process can utilize highly conserved common mechanisms, yet still be expressed as a highly individual process. We need to better understand how these mechanisms interact with the environment and the individual life history. We need to develop an alternative to the use of time as a measure of aging. And we need to reconcile the systems biology/gene network approach to complex phenotypes with the single gene/gene pathway approach currently used. Recent findings have made it possible to address these difficulties. The life span of any gradually aging animal can be viewed as being composed of a health span with low qx, and a senescent span with increasing qx. Longevity determinant mechanisms act in Drosophila by extending only the health span, while the accelerating decay of senescence-defense mechanisms likely underlies the increasing qx of the senescent span. There exists strong evidence indicating that genes or gene pathways do not act by themselves but rather as components of a gene interaction or gene expression network. We argue here that viewing senescence as the stochastic but non-random degradation of a network process allows us to conceptually explain the above difficulties. The oxidative stress/antioxidant defense gene network which we have characterized in S. cerevisae, is such a scale-free, non-homogeneous network. Its future expression is dependent on the prior exposure of the organism to oxidative stressors. This allows interaction with the individual life history. Specific highly connected network nodes will be sensitive tissue-specific targets, the loss of which likely underlies the shared aspects of senescence; while damage to sparsely connected nodes will be associated with individual aging variations. The rate at which different animals progress from displaying high function type of tissue-specific gene expression patterns to displaying low function type of tissue-specific gene expression patterns should be correlated with the effectiveness of their longevity determinant mechanisms and their senescence-defence mechanisms (e.g., resistance to oxidative damage, etc.). One interesting outcome of this effort is the provision of a mechanism suitable for the removal of time from the definition of aging and senescence.

Keywords (Optional): 
gene networks
health span
oxidative stress networks