Ageing per se increases susceptibility to lipid induced insulin resistance in rats

I am constantly on the lookout for studies on how biochemical mechanisms shift with age, the significance of these changes and how nutrition and lifestyle interact with them to potentially affect health.  Ageing itself is clearly an immensely complex process, and teasing out changes caused from ageing itself rather than known variables that effect health is difficult.

A recent paper by Francine Einstein et al. (1) examined how age influences susceptibility to free fatty acid (FFA) induced insulin resistance independent of phenotype in an animal model.  Rodents and humans experience an increase in FFA with age, and FFA elevation is a characteristic of visceral adiposity that often accompanies obesity.  This can trigger an increased secretion of cytokines, leading to a proinflammatory milieu and insulin resistance.  But does the ageing process alter some of these pathways itself?

F344 x BN rats divided into 3 groups: one fed ad libitum and young (3 months old) (YAL), one fed ad libitum and old (17-21 months) (OAL), and one calorie restricted old group (17-21 months old) that consumed 55% of ad libitum groups since 5 months old (OCR).

The calorie restriction protected against weight and visceral fat gain, as the YAL and OCR groups were similar in these measures, but the OAL rats were much greater in these 2 aspects as well as insulin, as expected.  The OAL group also had greater free fatty acids compared to the YAL but not OCR groups.

So these phenotype and metabolic markers are similar between young, overfed rats and old calorie restricted rats.

Hyperinsulinemic-euglycemic clamp experiments were performed, with each group of rats being divided further into treatments with Intralipid (triglyceride emulsions to induce insulin resistance) or a saline control.

The authors found that insulin concentrations and insulin response to saline were similar in the YAL and OCR rats.  However upon the lipid infusion, OCR rats developed insulin resistance faster than YAL rats: glucose production rose faster and uptake slowed faster in the OCR group.  In both the OCR and OAL groups, glucose production increased in parallel throughout the clamp, but the slope did not change in the YAL group.  These results suggest that ageing itself increased the susceptibility of the rats to FFA induced insulin resistance. The OAL rats were already maximally insulin resistant so the lipid challenge did not significantly alter these measures.

Gene expressions of the following cytokines were studied following the clamps: AT, resistin, leptin, TNF-alpha, PAI-1, IL-6, and IL-18.  These may be involved in an inflammatory milieu, and insulin resistance in visceral and subcutaneous fat.  In visceral fat in these rats (infused with intralipid), PAI-1 and IL-6 were the only 2 significantly different- PAI-1 was increased in the calorie restricted group but not other 2 groups, and IL-6 was increased in both the calorie restricted group and old ad libitum group but not the young.  In subcutanous fat, PAI-1 was the only differentially expressed gene, increased in the old ad libitum group.

Macrophage infiltration in visceral and subcutaneous fat was assessed: the YAL group had the lowest macrophage % in both visceral and subcutaneous fat compared to the other 2 groups, which interestingly were not significantly different compared to one another.  This is an interesting and novel find that suggests that macrophage infiltration can be caused by some mechanism of ageing per se, independent of adiposity. It is previously understood that only increasing fat mass increases macrophage infiltration.

The results together suggest that in a context of old age, elevated triglycerides have a greater effect on certain proinflammatory mechanisms which more quickly results in insulin resistance.

Of note: this adds to our understanding of calorie restriction, showing that it isn’t able to slow all features of metabolic ageing.

Speculation

No practical advice can be taken from this study as it is in rats.  It is interesting to consider in the context of other research on lipids and insulin resistance.  This may suggest that proper nutrition and lifestyle grows more important with age because of mechanisms independent of obesity that can trigger a proinflammatory state more easily in the right context.  The factors that do this dependent of obesity are the most studied right now- compounding these with age may explain why metabolic diseases grow more severe with age, and partly why young populations are initially more resistant.

These results are not relevant to a healthy context, as elevated lipids in this and other studies do not effect insulin sensitivity immediately- moreso it is an exaggerated or chronic response that would do this, which may be triggered by overnutrition or features of metabolic syndrome (exposure to elevated FFA would obviously have to be consistent to progress to disease, not acute like in this study).  Because it isn’t immediate, the authors suggest that glycosylation, transcription factor expressions, and inflammatory pathways are the mediators.  These all involve pathways that could be shifted by ageing processes (and are somewhat related).  In support of inflammatory pathways, PAI-1 and IL-6 expressions in visceral fat (and IL-6 in subcutaneous) were increased in old rats but not young, independent of body weight and energy intake.  In other studies, these cytokines are linked with both obesity and ageing, as well as diseases such as type 2 diabetes and cardiovascular disease.

Reference

1. Einstein FH, Huffman DM, Fishman S, Jerschow E, Heo HJ, Atzmon G, Schechter C, Barzilai N, & Muzumdar RH (2010). Aging per se increases the susceptibility to free fatty acid-induced insulin resistance. The journals of gerontology. Series A, Biological sciences and medical sciences, 65 (8), 800-8 PMID: 20504893