Researchers Fight Cellular Senescence, Low-Grade Inflammation

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AMSTERDAM—Low-grade inflammation in older adults can impede immune responsiveness, and researchers have shed light on how this happens. They have developed a short-term treatment that blocks inflammation and boosts the immune response, an expert said at EULAR: the Annual European Congress of Rheumatology.

The findings were presented in a session on cellular senescence related to inflammation and rheumatic diseases that also included new findings on how targeting a certain protein could help reverse senescence in chondrocytes and help osteoarthritis patients.

Low-Level Inflammation

As people age, inflammation develops at low levels, not as high as that seen in rheumatic diseases, but with effects nonetheless, said Arne Akbar, PhD, professor of immunology at University College London and associate of the Institute of Healthy Aging. This can result in reactivation of viruses that someone had already developed immunity to, such as chickenpox. This immune senescence tends to result from DNA damage caused by reactive oxygen species, ionizing radiation or ultraviolet radiation, Dr. Akbar said.

“Senescence is there to prevent cells with damaged DNA from proliferating,” Dr. Akbar said. If the cells did spread, there would be a risk of malignancy.

In a second phase, the cell attempts to repair the damage, using a cluster of proteins around damaged areas. If the repairs are made, the cell can go back to its normal functions. But if not, in a third stage, kinases are activated, leading to growth arrest of the damaged cells.

Dr. Akbar

“Senescent cells are not just useless cells that sit around doing nothing,” Dr. Akbar said. “They’re actually quite inflammatory,” bringing on a phenomenon known as inflammaging. “They secrete a whole range of inflammatory mediators, and that’s thought to be because [the body is] trying to get the immune system to come along and eradicate those cells or to get some tissue remodeling associated with damage in those cell types.”

The researchers in the Akbar group have found a clear divide in the response to immune skin challenges between younger and older subjects. But they have found this isn’t due to a lower number of memory T cells, but seems to be because of differences in the skin environment. They have also found the accumulation of senescent fibroblasts in the skin during aging is correlated with lower clinical scores on immune skin challenges.¹

Dr. Akbar’s team wondered: Is there a way to block this inflammation and bring about a more robust immune response?

As people age, an inflammation develops at low levels, not as high as tha t seen in rheumatic diseases, but with effects nonetheless, said Arne Akbar, PhD.

Losmapimod Study

In recent work, the researchers injected older adults with varicella zoster vaccine (VZV), measured the immune response and assigned a clinical score.² Two to three months later, they treated patients with the p38 mitogen-activated protein (MAP) kinase inhibitor losmapimod, followed by another VZV injection four days later, and another clinical score was calculated.

They found the clinical scores were significantly greater after losmapimod treatment than before (P<.0003). Also, by studying non-responders and responders, they found an elevated C-reactive protein (CRP) level seemed to identify the individuals who responded best to the treatment. They found a significant drop in CRP among these responders, he noted.

“This suggests the amount of systemic inflammation these individuals had before the challenge is related to their decreased initial immune response,” he said.

Dr. Akbar said the findings, once further explored and refined, could mean new therapeutic avenues for older adults with low-grade inflammation.

“If you block inflammation short term, you can increase the memory responses in older people,” he said. “This is going to be relevant for cancer therapy where you short-term-block inflammation. It’s going to be relevant, potentially, for vaccination, where you might be able to block inflammation in the short term in older people to open up a window of opportunity to let their immune systems respond. But these are all questions for the future.”

Cx43 Studied

In another presentation, Marta Varela-Eirin, MS, a PhD student at the Institute of Biomedical Research A Caruña in Spain, discussed work at her lab exploring a way to combat the senescence of chondrocytes, restricting cartilage regeneration and favoring the progress of osteoarthritis.³

They measured levels of the trans­membrane channel protein, connexin43 (Cx43), in mesenchymal stem cells and chondrocytes from donors with osteo­arthritis, finding the protein acts to regulate the reversion of chondrocytes to a state that is less differentiated.

“Overactivity of Cx43 in the membrane largely maintains this stem-like phenotype,” she said. The findings show that Cx43 is a worthwhile target in OA.

“Cx43 targeting fosters a pro-regenerative environment in OA,” Ms. Varela-Eirin said. “Downregulation of Cx43 promotes cell redifferentiation and is enough to restore the normal chondrocyte phenotype, decreasing senescence and the synthesis of catabolic factors.”

Thomas R. Collins is a freelance writer living in South Florida.

References

1. Aguis E, Lacy K, Vukmanovic-Stejic M, et al. Decreased TNF-α synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J Exp Med. 2009 Aug 31;206(9):1929–1940.
2. Vukmanovic-Stejic M, Chambers ES, Suárez-Fariñas M, et al. Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation. J Allergy Clin Immunol. 2017 Nov 17. pii: S0091-6749(17)31766-9.
3. Varela-Eirin M, Varela-Vazquez A, Paino C, et al. Targeting chondrocyte plasticity via Connexin43 modulation attenuates cellular senescence in osteoarthritis (abstract OP0223). Ann Rheum Dis. 2018 Jun 14;77(suppl):A160.