Impaired immune surveillance accelerates accumulation of senescent cells and aging
Ovadya Y, Landsberger T, Leins H, Vadai E, Gal H, Biran A, Yosef R, Sagiv A, Agrawal A, Shapira A, Windheim J, Tsoory M, Schirmbeck R, Amit I, Geiger H, Krizhanovsky V. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun. 2018 Dec 21;9(1):5435. doi: 10.1038/s41467-018-07825-3. PMID: 30575733; PMCID: PMC6303397.
Cellular senescence is a component of ageing that prevents damaged cells from proliferating and spreading that damage. Senescent cells are normally removed by the immune system and cells in that tissue regenerate. Senescence is also part of ageing and the efficiency of senescent cell removal decreases with age leading to an accumulation of senescent cells. With accumulation, the beneficial effects of senescence are outweighed by its negative effects.
Perforin-mediated granule exocytosis is necessary for immune surveillance of senescent cells in damaged livers. This study used perforin knockout mice to understand the consequences of impaired immune surveillance.
Results
The results showed that perforin deficiency accelerates senescence with age. In WT mice senescent cells made up 10% of the examined tissue while in the preforin knockout mice, it was 43% at 24 months. The expression of p16, another senescence marker, increased more in the KO mice than the WT. This senescence increase was tested with a number of other known senescence markers and shown to be consistent.
Along with the increase in senescent cell numbers, there was also an increase in age-dependent chronic inflammation with increased cytokine expression and more tissue-infiltrating immune cells. In 24 month-old mice there was an increase in serum cytokine levels and pro-inflammatory factors, but not in 2 and 12 month-old mice. The accumulation of senescent cells in tissues is accompanied by an increased inflammatory response.
Loss of perforin also resulted in age-related disorders like fibrosis in various organs, loss of the subcutaneous fat layer, and loss of hair follicles. An examination of their blood for tissue damage markers found tissue damage in internal organs as well as increased urea levels, probably from kidney damage. The KO mice were less active and had poorer grip strength and coordination that the WT mice. Further, these mice also had a decreased lifespan than the WT mice.
They also used a mouse with the LMNA gene mutation which resulted in senescent cell accumulation. These mice, when crossed with those with the preforin deficiency, acquired the deficiency and their lifespans were shorter than the mice with just the LMNA gene mutation. This suggests that despite an increased senescent cell burden, a functioning immune surveillance system can help to slow senescence-induced ageing.
Senolytic treatment
Using the ABT-737 senolytic resulted in decreased senescent cell burden, reduced inflammation and immune cell infiltration, and increased activity and lifespan. The treatment drove the expression of SASP genes down to levels found in young mice, counteracting the effect of ageing.
In the mice with the LMNA mutation, treatment extended their lifespan and decreased the senescent cell burden and cytokine levels.
If senolytic treatments are able to preserve the benefits of senescence, they could be part of therapeutics for age-related diseases and ameliorate the negative effects of ageing.