Senolytic Therapies to Clear Senescent Cells Should Benefit Cancer Patients

It is well known that the present dominant approaches to cancer therapy - meaning toxic, damaging chemotherapy and radiotherapy, only slowly giving way to immunotherapy - produce a significant burden of senescent cells. Indeed, forcing active cancer cells into senescence is the explicit goal for many treatments, and remains an aspirational goal for a large fraction of ongoing cancer research. Most senescent cells self-destruct, or are destroyed by the immune system, but some always linger - and more so in older people, due to the progressive incapacity of the immune system. An immune system that becomes ineffective in suppressing cancer will be similarly ineffective when it comes to policing tissues for senescent cells.

An increased burden of lingering senescent cells is a good deal better than progressing to the final stages of metastatic cancer, that much is true, but those who undergo chemotherapy understand that it is the second worse option on the table. It has a significant cost, even when completely successful. Cancer survivors may lose as much as a decade of life expectancy, and have a higher risk of suffering most of the other chronic diseases of aging. These consequences are most likely due to the presence of additional senescent cells generated by the treatment, over and above those produced over the course of aging.

The open access paper here provides supporting evidence for (a) the presence of senescent cells following radiotherapy to be harmful to patients, and (b) the removal of those errant cells to be beneficial, reversing the harms done. Senescent cells are in many ways the ideal type of damage to occur during aging: their inflammatory secretions actively maintain a harmful state of cellular metabolism in the surrounding tissue, and that stops the moment they are destroyed. Destruction is far easier to achieve than repair of structures or delivery of replacement parts, and this is perhaps one of the reasons why senolytic therapies to remove senescent cells are the first form of rejuvenation therapy from the SENS portfolio to be developed in earnest.

Restored immune cell functions upon clearance of senescence in the irradiated splenic environment

Cellular senescence is a complex phenotype observed in diverse tissues at distinct developmental stages. In adults, senescence likely acts to irreversibly prevent proliferation of damaged cells. Senescent cells appear during chronological aging, aberrant oncogene expression, and exposure to DNA damaging agents. Expression of the tumor suppressor p16INK4a increases with age in numerous mouse and human tissues and, thus, considered a reliable marker. Exposure to ionizing radiation (IR) leads to delayed increase in p16INK4a expression in mice tissues and cancer-treated patients

Senescent cells accumulate in tissues and secrete a range of cytokines, chemokines, and proteases known as the senescence-associated secretory phenotype (SASP). Why senescent cells accumulate in vivo remains unclear. One theory suggests senescence accumulates with a decline in immune functions with age. While senescent cells support wound healing, accumulation of senescent cells also appears to contribute to tumor growth and development of age-associated diseases. Significantly, genetic or pharmacological elimination of senescent cells reverses the onset of aging and associated pathologies in mice. Removing senescent cells reduces some side effects of chemotherapy and mitigate IR-induced premature aging in murine hematopoietic stem cells.

We previously observed irradiated mice developed impaired lymphopoiesis in the bone marrow, an effect both cellular nonautonomous and dependent on p16INK4a. Our current study sought to investigate whether IR-induced p16INK4a expression interfered with immune cell function. We provide evidence that exposure of mice to ionizing radiation (IR) promotes the senescent-associated secretory phenotype (SASP) and expression of p16INK4a in splenic cell populations. We observe splenic T cells exhibit a reduced proliferative response when cultured with allogenic cells in vitro and following viral infection in vivo.

Using p16-3MR mice that allow elimination of p16INK4a-positive cells with exposure to ganciclovir, we show that impaired T-cell proliferation is partially reversed, mechanistically dependent on p16INK4a expression and the SASP. Moreover, we found macrophages isolated from irradiated spleens to have a reduced phagocytosis activity in vitro, a defect also restored by the elimination of p16INK4a expression. Our results provide molecular insight on how senescence-inducing IR promotes loss of immune cell fitness, which suggest senolytic drugs may improve immune cell function in aged and patients undergoing cancer treatment.