Identification of lipid mediators provided by autophagy that polarize anti-inflammatory macrophages

Active: 2020.03.01 - 2021.09.30
UK SPINE Scientific Liaison: Monica Spisar

Adipose tissues play a crucial role in maintaining systemic metabolic homeostasis. During aging, the metabolic function of adipose tissue is impaired. The acute deletion of autophagy in mature adipocytes has recently been shown to lead to an increased production of lipid peroxides correlated to animal life span, prompting inquiry into the relative influence of adipocyte autophagy on aging.

Aging is associated with changes in lipid metabolism across several mammalian and non-mammalian species. To elucidate the origin of age-related changes in lipid metabolism, the contribution of autophagy in adipose tissue aging will be interrogated by assessing autophagy levels in mature adipocytes during aging in mice and in human donors (aged 30 to 65 years).

In parallel, an opportunity to use lipid species to mitigate biological aging will be explored. Chronic low grade inflammation is a common denominator for several age-related diseases; targeting this inflammatory process addresses these pathologies simultaneously. Altering the inflammatory status of macrophages through the addition of specific lipid species may have merit as a potential therapeutic approach to alleviating inflamm-aging. The use of lipid species as therapeutics in modern medicine is fairly unexplored and may allow expansion into a novel class of therapeutics.

Tissue macrophages take a central role in the aged immune system, controlling inflammatory processes. Preliminary data supports the hypothesis that FFA release from autophagy-deficient adipocytes may control macrophage polarization during distal inflammation, deleteriously shifting macrophage phenotype from an anti-inflammatory ‘M2-type’ to a pro-inflammatory ‘M1-type’. Lipid species which counteractively effect a shift toward the anti-inflammatory phenotype will be identified via lipidomic screening for differentially secreted lipids/free fatty acids (young, aged, autophagy-deficient) and the effects of differentially secreted lipids on macrophage polarization will be characterized.

Lipid species’ therapeutic potential will be verified in vivo by attempting to rescue effects observed in an intestinal inflammation model. Those lipid species will further be tested in murine models of aging. Following the current study, the next step would be to translate findings to human settings through supplementation studies in old human cohorts.

The two branches of this work will generate a new perspective on targeting metabolic alterations in aging, elucidating the options of modulating autophagy in mature adipocytes and of dietary supplementation of specific lipid species.