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Clinical Research
Can regulating cellular aging mitigate both cancer and heart disease?
New findings show cellular senescence is linked with cancer and cardiovascular disease, may offer new treatment options
The link between cellular aging and disease development is a key point of convergence where Houston Methodist researchers are developing an intervention that can slow or perhaps even reverse the progression of both cancer and cardiovascular disease (CVD). While research in the fields of CVD and cancer has made considerable advancements in prevention, screening and treatment, these diseases continue to be the leading causes of death across the world. Researchers at Houston Methodist have made a surprising discovery leading to the development of technology with the ability to rejuvenate human cells. Risk factors common to both diseases include smoking, obesity, older age, diabetes, gender, family history, hypertension, sedentary lifestyle, unhealthy diets and the gut microbiome. This extensive list of shared risk factors suggests a commonality in the biology and pathophysiology of the two diseases. Often, CVD and cancer co-exist in the same individuals. Patients with CVD are at an elevated risk of developing cancer, and conversely, those with cancer (particularly lung, breast and colon cancer) are at a higher risk of developing CVD. Research on cancer and CVD development has demonstrated senescence – the process of biological aging – to be a common link in the connection between these two disease progressions. Senescence (derived from the Latin word “senex” meaning “old”) was originally discovered serendipitously by Leonard Hayflick in 1961 when human fibroblast cells were irreversibly arrested in cell culture after serial passaging. At the cellular level, replicative senescence (RS), characterized by telomere shortening, is induced when cells reach the end of their replicative potential and enter a state of permanent growth arrest without apoptosis. RS is dependent on a biological clock. On the other hand, stress-induced premature senescence (SIPS) is triggered by cellular stressors such as DNA damage, smoking, diabetes mellitus, as well as cancer treatments. RS and SIPS differ in both molecular mechanisms as well as timeframes; the latter occurring within three to 10 days of exposure to the insults. Albeit in a state of cell cycle arrest, senescent cells can remain metabolically active and secrete cytokines, chemokines, growth factors and reactive oxygen species (ROS). This phenotype, referred to as the senescence-associated secretory phenotype (SASP), is induced by myriad stressors, including cancer treatments, pro-inflammatory cytokines and ROS. Although the precise role of senescence in the intersection of CVD and cancer development is unclear, SASP is hypothesized to be involved.
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The data suggest that ROS-mediated SASP induction can be a convergent point in the development of cancer and CVDs. ROS is pivotal to initiate telomere DNA damage and the subsequent SASP induction. However, because telomere DNA damage-induced SASP is irreversible once established, antioxidant therapy may be no longer effective to attenuate SASP during the progression of cancer and CVD. As such, understanding the regulation of SASP is the key to understand not only the interconnections between cancer and CVD, but also age-related diseases such as diabetes mellitus, Alzheimer’s disease, cataract and chronic obstructive pulmonary disease.”
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Nhat-Tu Le, PhD
Associate Professor of Cardiovascular Sciences Houston Methodist
In a review study published in Frontiers in Cardiovascular Medicine in 2021, Nhat-Tu Le, PhD, associate professor of Cardiovascular Sciences at Houston Methodist, detailed how SASP instigates CVD and the molecular mechanisms by which SASP is implicated in tumorigenesis. The functional role of senescence in cancer is controversial. SASP can be induced in both normal and cancer cells by stress, oncogenes or therapy. Interestingly, chemotherapy-induced senescence can condition senescent cancer cells to acquire senescence-associated stemness (SAS) which causes them to escape cell cycle arrest, become proliferative and promote both CVD and cancer. On the other hand, several mouse model and human specimen studies have demonstrated that senescent cardiovascular cells accumulate at the site of CVD and promote atherosclerosis, heart failure, arterial stiffness and hypertension.
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Nhat-Tu Le, PhD, associate professor of Cardiovascular Sciences
A key observation noted by Le is that SASP (which can be induced by both RS and SIPS) can lead to CVD as well as cancer. Conversely, both cancer and CVD provide feedback loops to activate SASP. “The data suggest that ROS-mediated SASP induction can be a convergent point in the development of cancer and CVDs. ROS is pivotal to initiate telomere DNA damage and the subsequent SASP induction. However, because telomere DNA damage-induced SASP is irreversible once established, antioxidant therapy may be no longer effective to attenuate SASP during the progression of cancer and CVD. As such, understanding the regulation of SASP is the key to understand not only the interconnections between cancer and CVD, but also age-related diseases such as diabetes mellitus, Alzheimer’s disease, cataract and chronic obstructive pulmonary disease,” said Le. Cancer treatments improve patient survival. However, the side effects can decrease patients’ quality of life. In many cases, the cancer cells become resistant to therapies and evolve to become even more aggressive, which defeats the purpose of the therapy. One interesting case in point is the strategy used in therapy-induced senescence whereby the therapy triggers cellular senescence to impede the growth of cancer cells. Surprisingly, therapy-induced senescence can induce SASP, which can lead to more potent cancer growth. Strategies focusing on modulating SASP appear to hold greater promise in the future – for advances in the treatment of both CVD and cancer. Strategies to selectively eliminate SASP cells via apoptosis induction seem to be particularly attractive, according to Le.
Priyanka Banerjee, Sivareddy Kotla, Loka Reddy Velatooru, Rei J Abe, Elizabeth A Davis, John P Cooke, Keri Schadler, Anita Deswal, Joerg Herrmann, Steven H Lin, Jun-Ichi Abe, Nhat-Tu Le. Senescence-Associated Secretory Phenotype as a Hinge Between Cardiovascular Diseases and Cancer. Front Cardiovasc Med. 2021 Oct 20;8:763930. doi: 10.3389/fcvm.2021.763930. The research activity related to this review was partially supported by grants from the National Institutes of Health (NIH) to JA (AI-156921).
Abanti Chattopadhyay, PhD, July 2022