An aged immune system drives senescence and ageing of solid organs
Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, Cui Y, Angelini L, Lee KA, McGowan SJ, Burrack AL, Wang D, Dong Q, Lu A, Sano T, O’Kelly RD, McGuckian CA, Kato JI, Bank MP, Wade EA, Pillai SPS, Klug J, Ladiges WC, Burd CE, Lewis SE, LaRusso NF, Vo NV, Wang Y, Kelley EE, Huard J, Stromnes IM, Robbins PD, Niedernhofer LJ. An aged immune system drives senescence and ageing of solid organs. Nature. 2021 May 12. doi: 10.1038/s41586-021-03547-7. Epub ahead of print. PMID: 33981041.
Ageing is one of the greatest risk factors for chronic diseases and ageing processing like senescence are a treatment target. Senolytics can be used to target senescence, but more work need to be done to understand what cells to target therapeutically.
Immunosenescence is the decline in immune function with ageing and the development of senescence that increase disease susceptibility and contribute to mortality.
ERCC1 is involved in the repair of DNA damage and reducing its expression can lead to the accumulation of oxidative lesions and senescent cells that then cause age-associated pathologies. This study used mice with ERCC1 removed from lymphoid organs that showed an accelerated ageing phenotype.
Immune system changes
The fraction of T cells was reduced in these mice at 4-5 months and T cells and B cells were reduced in older mutant mice unlike WT mice. Natural killer cytotoxicity was impaired in the mutant mice showing unhealthy immune ageing. Overall the ERCC1 deletion caused accelerated ageing in the mice immune system and shows that the immune system is vulnerable to DNA damage.
p16 and p21 were significantly reduced in B and T cells, natural killer cells and in macrophages along with an increase in SASP expression. p16 was found in the liver, kidneys, and the lungs. SA-β-galactosidase was increased in renal tubules and the liver.
The mutant mice were poorer muscle regeneration after injury as well as reduced grip strength. They also had a shorter lifespan than the control mice showing that an aged immune system can lead to the loss of homeostasis and damage in peripheral organs, negatively affecting lifespan.
Cell non-autonomous mechanism
The authors transplanted splenocytes from the mutant mice and two-year-old WT mice into p16Ink4a luciferase reporter mice. The mutant splenocytes had increased levels of luciferase signal than those from controls. SASP protein levels were also increased in the recipients of mutant splenocytes. These results show that senescent immune cells can drive ageing and affect lifespan.
Cell autonomous mechanism
Then they also transplanted splenocytes from young WT mice into the mutant mice. This resulted in the mutant mice showing reduced senescence and SASP factors levels. This also reduced p16 and p21 mRNA in mutant mice supporting the idea that a loss-of-function mechanism is involved in the inability of aged immune cells to suppress senescence.
Rapamycin rejuvenation
Rapamycin is used in elderly people to improve their immune response to flu vaccination. The mutant mice were treated with rapamycin and their immune response was improved and p16 and p21 expression was reduced suggesting a modulation of the gain- and loss-of-function mechanisms through which senescence drives ageing.
The study concluded that immune cells are vulnerable to endogenous DNA damage that can cause cell death or senescence if left unrepaired. Immunosenescence affects innate and adaptive immunity and drives senescence and age-related changes in solid organs.