The natural process of aging occurs on a cellular level, which affects tissue and organ function. As a result, our bodies lose the ability to easily complete daily movements and activities. Scientists believe aging occurs because of the shortening of telomeres at the end of a cell’s chromosome. Telomeres are small safeguard structures that prevent fraying of DNA and are critical in maintaining the integrity of the DNA complex. As we age, various factors can impact telomere shortening, including lifestyle choices and environmental stressors. The rate at which telomeres shorten directly correlates with the rate of aging. Unfortunately, this biological phenomenon is associated with decline in cellular function. Different ways to slow aging or telomere length is through healthy diet, exercise, and stress management. Currently, scientists are working to find ways to slow this process or reverse it.
Although slowing the biological clock may help improve longevity, disease can still occur. A major limitation to prolonging life is that individuals are more at risk of cancer. Interestingly, cancer is the result of mutations within cells which drive rapid proliferation. Cancer is commonly referred to as the “disease of aging”. In addition, as we age, our immune systems also decline and fail to effectively fight disease. Therefore, not only are aged patients more at risk of disease but are less likely to have an adequate immune response. Many researchers are investigating ways to improve immunity in older patients by learning more about the aging process. Novel cancer immunotherapies that target the immune system are of special interest to determine how aged patients respond.
A recent article in Nature Cancer, by Dr. Nicola Vannini and others, found that aging limits the efficacy of an engineered immune cell therapy, known as chimeric antigen receptor (CAR)- T cell therapy. Specifically, CAR-T cell therapy is an immunotherapy that takes T cells, responsible for targeting infections, and engineering them to recognize a specific marker on tumor cells. The engineered cells are then reinfused back into the patient and can target the tumor. Vannini is a professor and researcher at the University of Lausanne. His work focuses on cell activity, function, and energy consumption in the presence of cancer.
Vannini and his team found that the mitochondria, the organelle within the cell responsible for energy production, had lower activity and functioned less in aged mice. The use of mice helps researchers understand the biological mechanisms of therapies before bringing them to clinical trial for humans. Mice are often used because their immune systems are closely linked to ours. Further investigation indicated that a drop in nicotinamide adenine dinucleotide (NAD) levels, which is a molecule necessary for function of mitochondria and production of cellular energy. To counter low levels of NAD, researchers increased NAD by downregulating expression of a protein known to suppress NAD. As a result, CAR-T cell efficacy improved in aged immune systems. Scientists also used NAD-boosting compounds from the clinic to confirm the effects they were observing.
The fundamental discovery that NAD levels directly impact CAR-T cell therapy is groundbreaking. Through increased levels of NAD, investigators can reshape immune cell landscape and better inform clinicians how to treat aged patients. This finding will improve personalized medicine and promote the idea of age-conscious immunotherapy.
Article, Nature Cancer, Nicola Vannini, University of Lausanne
