How Might Deficit Accumulation Give Rise to Frailty?

Frailty is a multiply determined vulnerability state. People who are frail are at risk of many adverse health outcomes, including death. For any individual, this risk can only be expressed probabilistically. Even very fit people can suddenly die or become catastrophically disabled, but their risk of both is much lower than a very frail person, who might nevertheless suddenly succumb without worsening health. Frailty occurs with ageing, a stochastic, dynamic process of deficit accumulation. Deficits occur ubiquitously at subcellular levels, ultimately affecting tissues, organs and integrated organ action, especially under stress. Some people are disposed to accumulate deficits at higher rates, but on average, deficit accumulation varies across the life course and likely is mutable. In this way, the clinical definition of frailty is distinct from the statistical definition, which sees frailty as a fixed factor for an individual. Recent, early animal work links subcellular deficits to whole body frailty. In humans, clinically detectable health deficits combine to increase the risk of adverse health outcomes. The rate of deficit accumulation occurs with remarkable regularity around the world, as does a limit to frailty. Of note, when 20+ deficits are counted, these characteristics are indifferent to which deficits are considered. The expression of risk in relation to deficit accumulation varies systematically. For example, at any given level of deficit accumulation, men are more susceptible to adverse health outcomes than are women. Likewise, in China, the lethality of deficit accumulation appears to be higher than in Western countries. In consequence, it may be necessary to better distinguish between frailty and physiological reserve; the latter may apply chiefly in relation to microscopic deficits. The expression of frailty risk in relation to deficit accumulation depends on the environment, including both the physical and social circumstances in which people find themselves.