Reversing the Age-Related Loss of Eosinophils in Visceral Fat Reduces Chronic Inflammation and its Consequences

It is well known that visceral fat tissue is an important source of the chronic inflammation that drives the onset and progress of all of the common age-related diseases. This is normally discussed in the context of excess visceral fat, given the high prevalence of overweight individuals in our modern society of cheap calories and too little exercise. Visceral fat encourages the creation of senescent cells and their inflammatory secretions, but also rouses the immune system to inflammation via a range of other mechanisms. Overweight individuals have a shorter, less healthy life with higher lifetime medical expenses as a result.

These mechanisms are not only an issue in overweight individuals. As noted in today's research materials, even without excess visceral fat, there is a growing imbalance between the pro-inflammatory (macrophage) and anti-inflammatory (eosinophil) immune cell populations resident in visceral fat tissue. This contributes to age-related chronic inflammation, and thus disease and mortality. Having more visceral fat certainly makes the situation worse, but thin people do not remain immune to the harms.

Interestingly, researchers here demonstrate that an eosinophil cell therapy can reverse this process, and bring inflammatory fat tissue back under control. It remains to be seen as to how long this benefit lasts. Is it akin to first generation stem cell therapies in which the transplanted cells reduce inflammation via signaling that influences native cell behavior, but do not survive for long, or do the eosinophils survive to produce a lasting benefit? The former seems more plausible.

Age-related impairments reversed in animal model

For many years scientists speculated that chronic low-grade inflammation accelerates aging processes and the development of age-related disorders. Researchers have now demonstrated that a certain kind of immune cells, known as eosinophils, which are predominantly found in the blood circulation, are also present in belly fat of both humans and mice. Although classically known to provide protection from parasite infection and to promote allergic airway disease, eosinophils located in belly fat are responsible to maintain local immune homeostasis. With increasing age the frequency of eosinophils in belly fat declines, while the number of pro-inflammatory macrophages increases. Owing to this immune cell dysbalance, belly fat turns into a source of pro-inflammatory mediators accumulating systemically in old age.

In a next step, the researchers investigated the possibility to reverse age-related impairments by restoring the immune cell balance in visceral adipose tissue. "In different experimental approaches, we were able to show that transfers of eosinophils from young mice into aged recipients resolved not only local but also systemic low-grade inflammation. In these experiments, we observed that transferred eosinophils were selectively homing into adipose tissue." This approach had a rejuvenating effect on the aged organism. As a consequence, aged animals showed significant improvements in physical fitness as assessed by endurance and grip strength tests. Moreover, the therapy had a rejuvenating effect on the immune system manifesting in improved vaccination responses of aged mice.

Eosinophils regulate adipose tissue inflammation and sustain physical and immunological fitness in old age

Adipose tissue eosinophils (ATEs) are important in the control of obesity-associated inflammation and metabolic disease. However, the way in which ageing impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment partially restores ATE distribution in aged parabionts and reduces adipose tissue inflammation. Approaches to restore ATE distribution using adoptive transfer of eosinophils from young mice into aged recipients proved sufficient to dampen age-related local and systemic low-grade inflammation.

Importantly, restoration of a youthful systemic milieu by means of eosinophil transfers resulted in systemic rejuvenation of the aged host, manifesting in improved physical and immune fitness that was partially mediated by eosinophil-derived IL-4. Together, these findings support a critical function of adipose tissue as a source of pro-ageing factors and uncover a new role of eosinophils in promoting healthy ageing by sustaining adipose tissue homeostasis.

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