Deficit accumulation as an explanation for ageing and frailty – from the subcellular to the substantial

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

Prof Susan Howlett is  also at Dalhousie, University, Canada in the Department of Pharmacology.d

A lot happens at the molecular and cellular levels as we age. A recent review in Cell  identified nine hallmarks of ageing, including genomic instability, mitochondrial dysfunction, cellular senescence and stem cell exhaustion.  These, of course, are intrinsically inter-related; the DNA damage that underlies the hallmark genomic instability accelerates with telomere shortening (another hallmark) and is associated with altered protein homeostasis (another hallmark still). This molecular and cellular deficit accumulation is now widely understood as the basis of how we age.

Ageing is also associated with the accumulation of macroscopically visible deficits across the lifespan. How what happens at the level of the cell scales up to what we see as symptoms, signs, diseases and disabilities is what we considered in our “New Horizons” paper on frailty.. We focused on the accumulation feature: that as damage goes unrepaired or unremoved (and as time goes by) the chance that it becomes macroscopically visible increases.  Exactly how this happens is not yet clear. Some insight comes from a study of how deficits accumulate in ageing wild type mice.  There, changes in cell function and structure were more closely related to deficit accumulation (counted in a frailty index) than they were to age.

Although vagueness is the friend of consensus, it is the enemy of information, so that writing at this general level is challenging.  Even so, several hypotheses flow from this work, such as the role that laboratory measures (which sit between the cellular and the macroscopically visible) might inform our understanding of ageing.  Some hint about this comes from the Newcastle 85+ study.  No one over the age of 85 was without macroscopic deficits. Even though many markers of immune senescence (an aspect of the ageing hallmark stem cell exhaustion) were individually associated with a high level of macroscopic deficit accumulation (frailty), no single relationship was strong. This, of course, is compatible with ageing being the accumulation of a variety of deficits. (Presumably accumulation of a single type of deficit would be what we call disease.)  Another hypothesis from this work is that the acceleration of deficit accumulation would arise when the processes that repair or remove deficits themselves become damaged.

If there is any merit to writing in a general way, it is as stimulus to synthesis.  That is done with greatest discipline when done mathematically.  The elements of intrinsic and extrinsic damage and failure of removal and repair that give rise to deficit accumulation can be construed formally. That project of formalizing deficit accumulation from cells on up is the subject of additional inquiries by our group.

Kenneth Rockwood and Susan Howlett are authors of the latest New Horizons article in Age and Ageing journal: New Horizons in Frailty: Ageing and the Deficit Scaling Problem.