Intrauterine programming of ageing

Abstract

Ageing is an unavoidable corollary to being alive; the most intuitive interpretation of ageing being that it is the consequence of progressive body degeneration. In agreement with this, current models propose that ageing occurs through a stepwise accumulation of DNA damage, which ultimately limits the regenerative capacity of tissues. On the other hand, there is increasing evidence that fetal distress can influence the development of disease in adult life, a phenomenon known as 'intrauterine programming'. The extent to which an intrauterine exposure to DNA damage can compromise lifespan remains unclear. My group has recently generated a murine model of a human syndrome linked to defective DNA repair and observed that these animals age prematurely, but the accumulation of DNA damage is restricted mostly to the embryonic period. Here, I discuss the implications of this finding and propose that ageing can be influenced by fetal distress.

Figure 1

Intrauterine programming of ageing. The stresses to which embryos are subjected during development can determine the onset of ageing many years later.

Figure 2

Proposed mechanisms to explain an intrauterine contribution to ageing. First, stem cell (SC) pools or their niches can be compromised during development, leading to a permanent limitation on the capacity of the tissues to regenerate in adult life. Second, the epigenome of embryonic cells can be altered by stress signals, which might permanently alter their transcriptome in both a stochastic and a programmed manner (that is, by dampening the IGF1/GHR axis, which is a charcateristic of ageing tissues). Moreover, the altered epigenetic landscape might have a lasting effect that renders chromatin more susceptible to breakage. GHR, growth hormone receptor; IGF1, insulin-like growth factor 1.

Oscar Fernandez-Capetillo