Immune System becomes Overactivated in the Old Age

The absence of a critical signaling protein in particular immune cells can cause a variety of age-related disorders in young mice, according to RIKEN researchers. This discovery could eventually aid in the development of new treatments for age-related disorders. Aging is harsh on our immune system, causing over-activation and inflammation even when there are no pathogens in sight. This chronic, low-grade inflammation, known as inflammaging, destroys tissue, leaving elderly individuals more susceptible to infection and a variety of ailments such as cancer, type 2 diabetes, and heart disease.

T cells—help immune system, respond to, and remember specific pathogens—go into overdrive during inflammation, producing inflammatory substances such as cytokines and chemokines. This is referred to as T cell senescence.

“People often have the impression that aging makes cells less active,” says Takashi Saito of the RIKEN Center for Integrative Medical Sciences. “However, some aged immune cells enter an activated phase, and the resulting inflammaging can give rise to various age-dependent diseases.”

A signaling molecule known as receptor-interacting protein kinase 1 (RIPK1) regulates cell death via two distinct pathways, depending on the chemicals with which it interacts. Recent research has discovered that people with RIPK1 deficiency are more prone to inflammatory diseases.

Now, Saito and colleagues have created mice that lack RIPK1 just in their T cells. These mice developed inflammatory disorders at an early age and died substantially sooner than normal mice. Surprisingly, T cells missing RIPK1 behaved similarly to T cells from elderly mice. The findings have been published in the journal Science Advances.

The researchers discovered how this premature aging occurs. When RIPK1 is absent, two chemicals, caspase-8 and RIPK3, cause an overactivation of the cell-growth regulator mTORC1. This increases T cell senescence by increasing the expression of senescence-related genes, which results in the production of different cytokines and chemokines.

This mechanism was unexpected. “Caspase-8 and RIPK3 are well known to induce cell death,” says Saito. But we’ve shown that they also help to activate mTORC1 and induce inflammaging in cellular senescence.

This discovery opens up the possibility of finding new ways to treat inflammaging. “We could target caspase-8 and RIPK3 to counteract inflammaging induced by T cell senescence,” says Saito.

Another surprise was that when the researchers implanted the senescent T cells into normal mice, they reverted to normal, non-senescent T cells, demonstrating that environmental factors play a role in regulating T cell senescence.

The researchers are currently looking into what happens before RIPK3 and caspase-8 are activated. They also aim to investigate the environmental conditions that allow senescent T cells to return to normal T cells.

Source Link