Vaccination as a Limited Option for Removal of Senescent Cells

In today's open access paper, the authors demonstrate a form of vaccination against a surface marker that appears on a subset of senescent T cells that reside in fat tissue, thus directing the rest of the immune system to attack and destroy these cells. There is good evidence for excess fat tissue to result in an increased burden of senescent cells, which disrupt metabolism via the generation of inflammatory signals. A novel branch of medicine is under construction, based on senolytic therapies capable of selectively destroying senescent cells in aged tissues. The growing numbers of senescent cells in older people (and even larger numbers in older obese people) contribute to near all conditions of aging. Removing them has proven to be very beneficial in animal studies, reversing the progression of numerous age-related diseases.

A global, always-on mechanism to remove senescent cells has been shown to improve health and longevity in mice, but is probably not a good idea for human medicine. Senescence is a harmful process only when it runs awry, when senescent cells accumulate over time. Senescent cells are constantly created in a youthful metabolism, and serve useful purposes in suppression of cancer, wound healing, and other processes. They are near all rapidly destroyed, either by the immune system or by programmed cell death mechanisms. Only when they linger are they problematic, as starts to happen with aging. A vaccine that provoked constant, efficient destruction of all senescent cells (if such a thing was possible) would probably negatively impact regenerative capacity, at the very least.

In this case, it is possible to argue that the senescent T cells found in fat tissue, and particularly in excessive fat tissue deposits, serve no useful purpose. More work would need to be done to prove that point, but it is not an unreasonable hypothesis. Other populations of senescent cells may also exhibit distinctive surface markers and consistently harmful behavior, and thus also be good targets for a vaccination approach to therapy. This type of therapy is an interesting proposition, but may ultimately fail the cost-benefit analysis when compared with the much simpler strategy of periodic dosing with a mix of senolytic compounds that kill a sizable fraction of all senescent cells. Whether or not that is the case rather depends on the details, which will emerge over time as the field progresses.

The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice

Senescent cells produce proinflammatory and matrix-degrading molecules, which harm their surrounding nonsenescent cells. Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction and promote healthy aging and the removal of senescent cells by direct killing, either by apoptotic (senoptosis) or nonapoptotic (senolysis) methods, is an effective serotherapeutic approach. In the genetic model, INK-ATTAC mice, to undergo the inducible elimination of p16Ink4a-expressing cells, these mice in which p16Ink4a-positive senescent cells were eliminated exhibited a long life span and the attenuation of several aging phenotypes in white adipose tissue, the heart, and the kidney.

Senescent cells accumulate in fat in aging, and exercise-mediated reduction as well as genetic clearance improved glucose metabolism or lipotoxicity, respectively. Senescent T cells (referred to as senescence-associated T cells; SA-T cells), defined as CD4+ CD44high CD62Llow PD-1+ CD153+ cells, accumulate in visceral adipose tissues (VAT) in obese individuals and produce proinflammatory cytokines, causing chronic inflammation, metabolic disorders, and cardiovascular diseases. However, it is still unknown whether the selective depletion of senescent T cells can attenuate the age-related pathological changes.

Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10-11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of vaccinated mice, accompanied by improved glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the vaccinated mice successfully reduced the number of senescent T cells.

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