The role of cellular senescence in aging and disease
Written by Michael Seringer
The study of space radiation and naked mole rats has helped UT Health Science Center San Antonio researchers uncover mechanisms of human aging.
While working on a project for NASA a decade ago, Sandeep Burma, PhD, realized that cell senescence, a biological phenomenon characterized by irreversible arrest of cell division, might hold the key to the pathological effects of space radiation, including dementia and cancer.
Burma, professor of neurosurgery and of biochemistry and structural biology in the Long School of Medicine, was researching the cancer-causing effects of space radiation using mouse models of brain cancer. He found that these cancers were spurred by factors secreted by senescent brain cells caused by space radiation.
As cells divide over time, they accumulate damage to their DNA and other cellular components. Such damaged cells can enter a state of senescence in which they stop proliferating but remain active. While senescence prevents cancer in the short term, senescent cells promote aging and cancer in the long term. Investigators at UT Health Science Center San Antonio are working to uncover the mechanisms of cellular senescence and to design compounds to deplete these cells in order to potentially treat many age-related diseases and cancer.
“Cellular senescence is triggered by irreparable damage to DNA and cellular components, and shortening of the ends of chromosomes,” said Burma, who holds the Mays Family Foundation Distinguished Chair in Oncology.
“These damaged cells accumulate over time as cells divide or when they are subjected to stresses such as ionizing or UV radiation. Senescent cells generally exhibit large irregular shapes and cytoplasmic and nuclear changes and secrete factors that generate a senescence-associated secretory phenotype [SASP], which has an obvious role in the aging process.”
The two faces of cellular senescence
Cellular senescence has been identified as a critical process in various physiological and pathological contexts, including embryonic development, wound healing, tissue repair, cancer prevention and aging. Once a cell is damaged or has a cancer-causing mutation, senescence halts its ability to divide, effectively preventing the formation of tumors.
Ironically, the cancer defense system provided by senescence also can promote cancer over time.
“Senescence is primarily an anti-cancer barrier as it prevents cells with damaged DNA or shortened telomeres from proliferating,” Burma said. “However, senescent cells can paradoxically promote cancer via SASP factors, many of which can promote the proliferation, stemness, invasiveness or therapy resistance of cancer cells. SASP factors can also indirectly promote cancer development by suppressing anti-tumor immunity.”
Burma’s research has demonstrated that treating glioblastomas, a type of brain tumor, with radiation results in the senescence of astrocytes near the tumor. The SASP factors secreted by these astrocytes, which are resistant to cancer therapy, can promote tumor recurrence after treatment. They can cause the glioblastoma cells themselves to become senescent. These senescent tumor cells have a similar expression of SASP, which can promote tumor resistance to therapy and thus recurrence. Understanding how SASP’s inflammatory and growth factors promote the proliferation and survival of cancer cells will lead to more effective cancer treatments with fewer side effects, he said.
In addition to secreting the SASP factors, some cancer cells have demonstrated the capacity to break free of senescence after therapy. These escaped cells either develop mutations that counteract the signals driving senescence or develop alterations that allow the cells to ignore the changes associated with senescence. These once-senescent cancer cells can continue to divide and grow, leading to tumor progression.
“Precancerous cells being held in check by senescence could escape senescence and re-proliferate, aggressively leading to cancer progression,” said Burma. “Similarly, tumor cells that have been rendered senescent by genotoxic therapy could escape after acquiring ‘cancer stem cell’ properties and give rise to an aggressive recurrence.”
Understanding these escaped cells could lead to the development of a “one-two punch” in cancer therapy in which genotoxic treatments are followed by a drug that kills senescent cells, termed a senolytic. Such a two-step approach aimed at selectively eliminating senescent cells from the body after the initial cancer treatment is complete may provide far more benefit to glioblastoma therapy.
SASP and the morbidities of aging
Senescent cell SASP factors are associated with multiple age-related diseases due to their role in promoting chronic inflammation and tissue dysfunction. The chronic inflammation caused by the SASP can contribute to the development and progression of various diseases including cardiovascular disease, diabetes, neurodegenerative disorders, osteoarthritis, autoimmune disorders and other conditions, said Daohong Zhou, MD, professor in the Department of Biochemistry and Structural Biology, director of the Center for Innovative Drug Discovery and associate director of drug development at the Mays Cancer Center at UT Health San Antonio.
The SASP is made up of secreted hormones, cytokines, chemokines and other molecules that induce inflammation. These SASP factors contribute to the development and progression of a range of diseases of aging. Likewise, SASP’s influence on inflammation and tissue dysfunction can contribute to the development and progression of various conditions associated with aging such as Alzheimer’s and Parkinson’s diseases, said Zhou.
director of drug development at the Mays Cancer Center, and professor in the Department of Biochemistry and Structural Biology
By targeting specific proteins within cells, Zhou’s research focuses on developing small molecules that can selectively kill senescent cells. The challenge in developing these small molecules, or senolytic therapies, is reducing the toxicity of compounds so that they remain therapeutic while minimizing side effects.
“The goal is a compound that patients can tolerate,” Zhou said. “It has to be really safe with minimal toxicity so people will not suffer from side effects. This is important to improving the quality of life during the human lifespan.”
Zhou’s research is taking advantage of small-molecule PROTACs (PROteolysis TArgeting Chimeras) to target and destroy specific proteins within cells, reducing the toxicity of potential therapies. PROTACs are a promising new tool in drug development allowing researchers to selectively eliminate disease-causing proteins that are challenging to target using traditional small molecules or antibodies.
Also at the forefront of research, Burma’s lab is actively investigating the use of senolytic therapy for ameliorating the effects of aging and treating cancer. He is focused on developing compounds that are effective at clearing out senescent cells while leaving behind the healthy ones.
“Senolytics generally target anti-apoptotic or pro-survival mechanisms that senescent cells upregulate to survive,” said Burma. “The basic premise here is that senolytics should clear out senescent cells but spare normal cells that do not upregulate these pathways.”
Burma points to a recent paper that demonstrates how the naked mole rat may hold the key to understanding the aging properties of cell senescence. These rodents are remarkable for their longevity compared to other small mammals of similar size. The naked mole rat, the longest living of all rodents, has a built-in mechanism for removing senescent cells. This ability to clear out senescence is responsible for the naked mole rat having an incredible 30-year average lifespan. The naked mole rat also demonstrates resistance to many age-related diseases, underscoring the potential of senolytic therapy for improving health and prolonging lifespan in humans.
