David Bernard

The age‐related decline in immunity reduces the effectiveness of vaccines in older adults. Immunosenescence is associated with chronic, low‐grade inflammation, and the accumulation of senescent cells. The latter express Bcl‐2 family members (providing resistance to cell death) and exhibit a pro‐inflammatory, senescence‐associated secretory phenotype (SASP). Preexisting senescent cells cause many aging‐related disorders and therapeutic means of eliminating these cells have recently gained attention. The potential consequences of senescent cell removal on vaccine efficacy in older individuals are still ignored. We used the Bcl‐2 family inhibitor ABT‐263 to investigate the effects of pre‐vaccination senolysis on immune responses in old mice. Two different ovalbumin (OVA)‐containing vaccines (containing a saponin‐based or a CpG oligodeoxynucleotide adjuvant) were tested. ABT‐263 depleted senescent cells (apoptosis) and ablated the basal and lipopolysaccharide‐induced production of SASP‐related factors in old mice. Depletion of senescent cells prior to vaccination (prime/boost) had little effect on OVA‐specific antibody and T‐cell responses (slightly reduced and augmented, respectively). We then used a preclinical melanoma model to test the antitumor potential of senolysis before vaccination (prime with the vaccine and OVA boost by tumor cells). Surprisingly, ABT‐263 treatment abrogated the vaccine's ability to protect against B16 melanoma growth in old animals, an effect associated with reduced antigen‐specific T‐cell responses. Some, but not all, of the effects were age‐specific, which suggests that preexisting senescent cells were partly involved. Hence, depletion of senescent cells modifies immune responses to vaccines in some settings and caution should be taken when incorporating senolytics into vaccine‐based cancer therapies.

Cellular senescence is induced by many stresses including telomere shortening, DNA damage, oxidative, or metabolic stresses. Senescent cells are stably cell cycle arrested and they secrete many factors including cytokines and chemokines. Accumulation of senescent cells promotes many age‐related alterations and diseases. In this study, we investigated the role of the pro‐senescent phospholipase A2 receptor 1 (PLA2R1) in regulating some age‐related alterations in old mice and in mice subjected to a Western diet, whereas aged wild‐type mice displayed a decreased ability to regulate their glycemia during glucose and insulin tolerance tests, aged Pla2r1 knockout (KO) mice efficiently regulated their glycemia and displayed fewer signs of aging. Loss of Pla2r1 was also found protective against the deleterious effects of a Western diet. Moreover, these Pla2r1 KO mice were partially protected from diet‐induced senescent cell accumulation, steatosis, and fibrosis. Together these results support that Pla2r1 drives several age‐related alterations, especially in the liver, arising during aging or through a Western diet.