How might health deficits in cells scale up to become clinically visible?

Prof Kenneth Rockwood is Director of Geriatric Medicine Research at Dalhousie University, Canada and serves on the International Advisory Panel of Age and Ageing journald

A July Age and Ageing paper on frailty considered how subcellular damage might “scale up” to lead to clinically detectable deficits. In December, a paper from Biogerontology addressed how deficits originate, and how they might scale.  The proposed answer appears to be powerful and offers some insights into how to think about frailty and disease in older adults.

The essential idea comes from queuing theory, a discipline of mathematics that analyses the behaviour of queues. At its simplest, the length of a queue depends on two factors: the rate at which people arrive at the queue, and the rate at which they can be processed. If more people arrive at the queue than can be processed, the queue grows; if fewer people arrive, or if the processing is very rapid, the queue shrinks.

The new paper makes the case that deficit accumulation can be viewed in the same way.  A deficit arises when damage is neither removed nor repaired (nor avoided, which is equivalent to instantaneous damage repair).  If there is a high rate of damage (equivalent to the number of people arriving at the queue) or repair of the damage is slow (equivalent to processing time; the term used in the paper is “recovery time”) then deficits accumulate.  The equation shows that deficit accumulation is a direct function of the rate of damage and the rate of repair.

Of course the equation itself is silent on from where damage arises, and in what recovery consists. It does not itself lend insight into which factors influence the rate of repair, and how they might vary. Even so, it allows candidate factors to be modelled in a new way, as co-variates in the equation, and in the large family of equations that have grown up to characterize such behaviour across a very wide range of applications. In its present form, the deficit accumulation equation is silent on mortality, or why the rate of deficit accumulation should be characteristic, or why the distribution of the frailty index should be skewed, with a long right tail, as it is in community-dwelling samples. These are consequences of whatever myriad processes give rise to what we see.

The most immediate consequence of considering that deficit accumulation might correspond to a queue is that extensive apparatus of queuing theory can be employed to a range of new investigations.  This is exciting, because a particular challenge of studying ageing is that the fundamental aspects of matter do not age.  Although at the scale of atoms we can detect decay, but rate of decay does not change, so formally, the atoms are not ageing.  Instead, ageing is the property of a system, and the tools we need to explore how systems behave oblige some part of academic geriatric medicine to make use of insights from physics, system biology and engineering mathematics, amongst other fields. This is not especially onerous for our discipline: every organ based subspecialty looks to sophisticated technologies to inform daily practice.

Another interesting consequence of the work is that it can address some of the tautology easily stumbled into in invoking “physiological reserve”.  Although controversy abounds in exactly how frailty should be operationalized, there is considerable consensus about key ideas of in what frailty consists. These are that frailty is reflected in a variable vulnerability to adverse health outcome of people of the same age, and that it becomes more manifest with a multiply determined decline in physiological reserves.  The new formulation offers us this: for people with a similar damage rates, variability in the number of deficits that they have arising as a function of variability in recovery time, a useful surrogate for physiological reserve.  It also allows us to work backwards to suggest that for people of a similar level of recovery time, variability in deficit accumulation reflects variability in the rate of damage to which they are exposed.  A March 2012 Age and Ageing paper on the higher rate of mortality amongst people with no deficits at baseline with the highest degree of social vulnerability, compared to those with the least level of vulnerability offers an example of how this insight might be employed.  Other candidates for systematic variation in the level of damage, or the rate of repair, include national economic indicators, explored in Age and Ageing in September 2013.  A June 2013 review in Cell provides a useful inventory of how other factors that give rise to genomic instability, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction or altered intercellular communication, amongst others, can lead to cellular and tissue ageing. As such factors become clinically measurable, this approach can offer a means of quantifying their impact on ageing, allowing some insight into how deficits in cells give rise to what we observe clinically.

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