The thymus is a tiny organ near the heart responsible for generating T cells of the adaptive immune system. Thymocyte cells are made in the bone marrow, migrate to the thymus, and undergo a process of exposure and selection that leads to mature T cells. The adaptive immune system needs a supply of new cells to make up the losses incurred due to damage and the Hayflick limit on replication. Unfortunately, the thymus atrophies with age; it is one of the earliest organs to reach a significant loss of function. Most 50-year olds have little active thymus tissue left, and a sizable component of the subsequent accelerating decline of the adaptive immune system takes place because it is denied sufficient reinforcements. It becomes ever more populated by senescent, exhausted, and malfunctioning T cells.
There are strategies that will absolutely, definitely regenerate the aged thymus, well demonstrated in animal models. None of them are all that practical for widespread use in medicine, or at least not palatable to those in charge of the regulation of medicine. Upregulation of FOXN1 via gene therapy regrows the thymus, but no delivery system other than direct injection has emerged to enable sufficient delivery to such a small organ without overloading and harming other tissues. Direct injection is not palatable because any sort of introduction of a needle into the inner organs of an aged individual has a small but meaningful rate of severe complications. This also rules out the use of KGF protein therapy, shown to regenerate the thymus in animal studies, but which cannot be introduced into humans at high enough levels via intravenous injections without causing unacceptable side-effects in other tissues.
Currently those working in the field of thymus regeneration are focused on a few different strategies. Firstly there are potential cell therapies that use cell populations known to home to the thymus, such as thymocytes and thymic epithelial cells. One can even engineer the cells, say to secrete KGF for example. Then there are a range of quieter and not yet successful efforts to find some clever way to use a small molecule or a biologic to tweak the metabolism of the thymus without upsetting any of the other tissues in the body. Existing targets, particularly those close to FOXN1, make that difficult to achieve. Lastly there is the Intervene Immune approach of tailored growth hormone therapy, which produces thymic restoration to a similar degree as observed following long term mild calorie restriction.
The good news for today is that someone is claiming to have found a viable small molecule approach to regeneration of the aged thymus that works via intraperitoneal injection in mice, a popular stand-in for intravenous injection. The treatment duration was quite short, only a few weeks. The number of mice per group is sadly low, 5 for some of the data, as low as 3 for some of the rest. That is low enough that I would want to see this replicated with 12 or more mice per group before taking it at face value. The small molecule in question is a free fatty acid receptor agonist, with the free fatty acid receptor GPR40 as the target; this agonism appears to compensate for a reduction in expression in this receptor, but how exactly this interacts with what is known of the FOXN1-centered biochemistry regulating thymic growth and activity remains to be seen. It could be as simple as reduced inflammation in thymic tissue, as reductions in inflammatory signaling are a known outcome of GPR40 agonism, but very little in biology tends towards being simple.
The thymus plays a crucial role in T-cell development and the establishment of cellular immunity. Thymic epithelial cells (TECs), which constitute the predominant stromal cell population in the thymus, are vital for maintaining thymic structure and function. With aging, the thymus undergoes gradual involution, characterized by a reduction in thymic volume, a decline in TEC numbers, and an accumulation of fibroblasts, adipocytes, and senescent cells within the thymic microenvironment. These changes result in decreased production of naïve T cells and reduced diversity of peripheral T-cell receptors (TCRs), ultimately compromising immune function in the elderly.
GW9508 is a selective agonist of GPR40, a receptor extensively studied in the context of metabolic diseases, and more recently, in relation to age-associated disorders. GPR40, also known as free fatty acid receptor 1 (FFAR1), is predominantly expressed in pancreatic β-cells and insulin-secreting cell lines, as well as in enteroendocrine cells, gustatory cells, immune cells, splenocytes, and the brain. Within immune system, GPR40 is implicated in regulating the functions of various immune cell, including keratinocytes, macrophages, and neutrophils. However, the role of GPR40 in senescent TECs has not been documented.
Here, GW9508, a selective agonist of GPR40, was used to treat aged C57BL/6J mice and aged iTECs model. The results indicated that targeted activation of GPR40 can activate the AMPK signaling pathway while inhibiting the ERK1/2-MAPK pathway, thereby enhancing the viability and restoring the function of aged iTECs. In vivo experiments in 17-month-old mice confirmed the effects of GW9508, consistent with cellular assays results, demonstrating that GW9508 effectively restored thymic function and facilitated structural recovery. Although thymus dysfunction begins relatively early in life, a recent study showed that it retains substantial protective capacity in adults, strongly supporting the notion that enhancing thymus function holds significant potential for improving T-cell function in older adults.
View the full article at FightAging
