Beyond hallmarks of aging - biological age and emergence of aging networks.

The hallmarks of aging have contributed immensely to the systematization of research on aging and have influenced the emergence of geroscience. The developments that led to the concepts of the hallmarks and geroscience were first marked by the proliferation of 'theories' of aging, mostly based on the experimental predilections of practitioners of aging research. Deeper consideration of the concepts of hallmarks of aging and geroscience leads to the quandary of whether a biological aging process exists beyond disease itself. To address this difficulty, a metric of biological age as opposed to calendar age is necessary. Several examples of biological age measured using similar assumptions, but different methods, exist. One of these, the frailty index was the first to successfully characterize aging in terms of loss of integrated function, and it is simpler than and superior to other constructs for measuring biological age. Though relatively simple in construction, the frailty index is rich conceptually, however, pointing to a network model of the aging organism. This network functions as a nonlinear complex system that is governed by stochastic thermodynamics, in which loss of integration leads to increasing entropy. Its structure transcends all levels of biological organization, such that its parts form hierarchies that are self-similar (fractal). The hallmarks of aging are simply nodes in the aging network, which can be found repetitively in various locations of the network. Stochastic thermodynamics implies that the aging system with higher entropy can exist in a multitude of possible microstates that are tantamount to high disorder with a high probability to assume a certain state. This explains the observed variability among aging individuals.