Why Do Old Flies Die?

Here is an interesting view on the process of final decline and fatal systems failure due to damage and maladaptive responses to damage that occurs at the end of aging:

As we get older we become more likely to get sick and, eventually, die. Although the underlying pathologies and major causes of death in elderly humans have been well documented, much less is known about the events leading to age-related death in the fruit fly Drosophila melanogaster - one of the premier model systems in aging research. What is the underlying pathology that limits the lifespan of a fly? Is it possible to predict when a fly will die based upon a loss of organ function? What accounts for the enormous variation in lifespan amongst individual flies within a population? Recently, we have identified a physiological phenotype preceding death in Drosophila that allows us to identify, in any given population, individuals that will die in the next few days.

In this work, we show that all individuals show an altered control of intestinal permeability a few days prior to death regardless of chronological age. Interestingly, these same individuals also showed a striking increase in the expression of inflammatory markers (antimicrobial peptides, AMPs) as well as systemic metabolic defects, including impaired insulin/insulin-like growth factor signaling (IIS). Importantly, we observed that chronologically age-matched individuals, from the same population, without altered intestinal permeability do not show major changes in these parameters with age. This discovery suggests that, in Drosophila at least, these different phenotypes are tightly linked to one another and to the end of life. Indeed, we could independently identify flies that would die within a few days by selecting for increased AMP expression, and these flies showed systemic metabolic defects, including impaired IIS, and intestinal barrier failure.

One interpretation of these findings, consistent with the 'hyperfunction theory of aging', is that the overactivity of AMPs is driving pathology and directly leading to death. Alternatively, increased AMP expression may represent a benign marker of impending death, which may result, in large part, from other factors such as a loss of intestinal homeostasis and/or systemic metabolic dysfunction.

As well as highlighting an important link between intestinal aging and organismal aging, this work may be telling us something about the very nature of the aging process itself. Our findings support a model where aging is composed of two consecutive phases, a first phase characterized by a growing likelihood of displaying intestinal barrier failure / inflammation / systemic metabolic dysfunction followed by a second phase leading to death. Remarkably, recent work [has] shown that intestinal cell death precedes organismal death in C. elegans, through a calcium-propagated necrotic wave. Furthermore, a chronic state of inflammation and the development of insulin resistance are key hallmarks of human aging and have been linked to multiple age-onset diseases. Therefore, our findings, in Drosophila, may provide insight into the relationships between intestinal homeostasis, systemic aging and disease susceptibility in mammals.

You might consider this in the context of past research that has shown that altering PGC-1 in intestinal tissues only, thereby apparently increasing stem cell activity and improving mitochondrial function in the intestine, is enough to increase life span in flies by up to 50%.

Link: http://impactaging.com/papers/v5/n8/full/100589.html

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