  We increasingly rely on the network approach to understand the complexity of
cellular functions. Chaperones (heat shock proteins) are key "networkers",
which have among their functions to sequester and repair damaged protein. In
order to link the network approach and chaperones with the aging process, we
first summarize the properties of aging networks suggesting a "weak link theory
of aging". This theory suggests that age-related random damage primarily
affects the overwhelming majority of the low affinity, transient interactions
(weak links) in cellular networks leading to increased noise, destabilization
and diversity. These processes may be further amplified by age-specific network
remodelling and by the sequestration of weakly linked cellular proteins to
protein aggregates of aging cells. Chaperones are weakly linked hubs [i.e.,
network elements with a large number of connections] and inter-modular bridge
elements of protein-protein interaction, signalling and mitochondrial networks.
As aging proceeds, the increased overload of damaged proteins is an especially
important element contributing to cellular disintegration and destabilization.
Additionally, chaperone overload may contribute to the increase of "noise" in
aging cells, which leads to an increased stochastic resonance resulting in a
deficient discrimination between signals and noise. Chaperone- and other
multi-target therapies, which restore the missing weak links in aging cellular
networks, may emerge as important anti-aging interventions.
