The research I'll note today involves genetic knockout of fatty acid-binding proteins in mice, something that appears to slow the development of metabolic disorders associated with excess fat tissue and aging - there is a lot more funding for investigation of the former cause as opposed to the latter cause, sadly. The work is, I think, chiefly interesting for mimicking some of the cellular effects of calorie restriction, while preventing some degree of the metabolic decline that accompanies aging, but achieving all of this without either extending life or improving the other usual functional measures of aging: loss of strength, cognitive decline, and so forth. In principle that sort of result should be quite hard to achieve, and indeed I can think of few lines of research in which this happens with any reliability in short-lived species such as mice. They are sensitive to environmental and genetic interventions, with very plastic life spans in comparison to those of longer-lived species such as our own. Anything that constitutes a significant improvement to health should also extend life.
Extending the duration of measures of health without extending life span is hard precisely because aging is determined by cell and tissue damage, a consequence of that damage, just like the decline of any complex machinery. There are only a few options when it comes to how to proceed: fix the root cause damage, try to compensate for loss of function by adding more capacity, or try to prevent secondary effects that result from the primary damage. Medicine to date has focused on the latter two options, which is precisely why it produces only marginal, incremental benefits. Making a damaged machine work well without repairing the damage is exactly as challenging as it sounds.
The genetic intervention carried out by the researchers in this paper has the look of a method of preventing secondary effects, some of those resulting from weight gain and fat tissue dysfunction in aging, by interfering in the processing of fats. That is no doubt an overly simplistic consideration. For example, we know that simple surgical removal of visceral fat significantly extends life span in mice, and yet the genetic approach here, that reduces weight gain, has no such outcome. A first thought is that it is possible that removal of fatty acid-binding proteins is causing harm in other areas of biochemistry, and thus shortening life even as it helps on the metabolic front. So while the researchers discuss their data as evidence of a decoupling of metabolic health and life span, and make a fair case, it may or may not be what is happening under the hood.
Scientists found that mice that lack fatty acid-binding proteins (FABPs) exhibit substantial protection against obesity, inflammation, insulin resistance, type 2 diabetes, and fatty liver disease as they age compared with mice that have FABPs. However, this remarkable extension of metabolic health was not found to lengthen lifespan. FABPs are escort proteins or "lipid chaperones" that latch onto fat molecules, transport them within cells, and dictate their biological effects. Previous work found that when FABP-deficient mice were fed high-fat or high-cholesterol-containing diets, they did not develop type 2 diabetes, fatty liver, or heart disease.
Metabolic health typically deteriorates with age, and researchers believe that this contributes to age-associated chronic diseases and mortality. Studies have shown that high-calorie diets impair metabolism and accelerate aging; conversely, calorie restriction has been shown to prevent age-related metabolic diseases and extend lifespan. In the new study, researchers examined metabolic function in multiple cohorts of FABP-deficient mice throughout their life. They found that FABP deficiency markedly reduced age-related weight gain, inflammation, deterioration of glucose tolerance, insulin sensitivity, and other metabolic malfunctions. This effect was more strongly observed in female than male mice. Surprisingly however, they did not find any improvement to lifespan or preservation of muscular, cognitive, or cardiac functions with age.
The researchers saw striking similarities between the alterations in tissue gene expression and metabolite signatures in the genetic model of FABP-deficiency developed for this study and the alterations that occur due to calorie restriction. The findings suggest that it may be possible to mimic part of the metabolic benefits of calorie restriction by targeting FABPs. In addition, by examining the molecular differences between these models, it may also be possible to identify other pathways that contribute to longer life span or alternative strategies to prevent metabolic diseases.
In this study, we have shown that the lipid chaperones FABP4/FABP5 are critical intermediate factors in the deterioration of metabolic systems during aging. Consistent with their roles in chronic inflammation and insulin resistance in young prediabetic mice, we found that FABPs promote the deterioration of glucose homeostasis; metabolic tissue pathologies, particularly in white and brown adipose tissue and liver; and local and systemic inflammation associated with aging. A systematic approach, including lipidomics and pathway-focused transcript analysis, revealed that calorie restriction (CR) and Fabp4/5 deficiency result in similar changes to the adipose tissue metabolic state, specifically enhanced expression of genes driving de novo lipogenesis and non-esterified fatty acids accumulation. Furthermore, CR was associated with reduced FABP4 in circulation, providing a potential molecular mechanism underlying its metabolic benefit.
The extension of metabolic health by Fabp deficiency is long-lasting even in aged female mice. However, despite the remarkable protection in glycemic control, insulin sensitivity, inflammation, and tissue steatosis in Fabp-deficient mice, we did not observe any change in the lifespan curves. We also did not detect preservation of cardiac, muscular, and cognitive functions. In females, there was even a mild decline in cardiomuscular function associated with Fabp deficiency during aging. These observations support the concept that, in higher organisms, significant improvements in metabolic tissue inflammation, metabolic tissue integrity, and systemic metabolic homeostasis may not necessarily lead to increased longevity.
Our studies with Fabp-deficient mice now provide genetic evidence in animal models that prolonged metabolic health, particularly glucose and lipid homeostasis, may be uncoupled from lifespan and maintenance of cardiac, muscular, and cognitive systems, which partially recapitulates the human pathophysiology observed during intensive glycemic control. Furthermore, it is intriguing that there is a considerable overlap between the unique lipidomic profile, especially in adipose tissue, of Fabp-deficient animals with those that have been subject to CR. Future studies exploring the similarities and distinctions between these models in multiple sites may provide additional insights into specific pathways and their regulation of healthspan and lifespan. Further exploration of the disconnect between metabolic health and longevity may also shed light on alternative therapeutic approaches against diabetes and possibly other metabolic diseases that are associated with aging as a risk factor.