Gene Networks, Individual Senescence, and Timeless Aging
R. Arking and C.N. Giroux
Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA
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.
Key words:
gene networks, senescence, health span, oxidative stress networks
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