The role of senescent cells in anti-aging medicine

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Not all senescent cells are harmful “zombies” that should be wiped out to prevent age-related disease, according to new research from UC San Francisco, which found that some of them are embedded in young, healthy tissues and promote normal repair from damage.

Scientists have now seen these cells in action in lung tissue, as well as other organs that serve as barriers in the body, such as the small intestine, colon and skin. When they used drugs called senolytics to kill these cells, injuries to lung tissues healed more slowly.

“Senescent cells can occupy niches with privileged positions as ‘sentinels’ that monitor tissue for injury and respond by stimulating nearby stem cells to grow and initiate repair,” said Tien Peng, MD, associate professor of pulmonary, critical care, allergy and sleep medicine, and senior author of the study, which appears in Science on October 13, 2022.

Aging cells can both damage and heal

Peng said it was understandable that scientists at first viewed senescent cells as purely detrimental. As people age, senescent cells accumulate that have characteristics of old, worn-out cells, including the inability to make new cells. Instead of dying like normal aged cells, they to live on, spewing a cocktail of inflammatory compounds that form the senescence associated secretory phenotype (SASP).

These factors are linked to Alzheimer’s disease, arthritis, and other age-related maladies including cancer. The catchy name “zombie cells” was coined for them.

Using senolytics that target and kill “zombie cells,” researchers made the exciting discovery that clearing senescent cells from animals thwarted or diminished age-related disease and extended the lifespan of the animals. Thereafter, a boom of activity ensued in research labs and pharmaceutical companies focused on discovering and refining more powerful versions of these drugs.

But killing off senescent cells has dangers, Peng said. For one thing, this current study showed that senescent cells also possess the ability to promote normal healing through activation of stem cell repair. “Our study suggests that senolytics could adversely affect normal repair, but they also have the potential to target diseases where senescent cells drive pathologic stem cell behavior,” said Peng.

Lighting up senescent cells

One major challenge to studying senescent cells is that biomarkers of senescence (such as the gene p16) are often quite sparse, making it difficult to detect the cells. In early experiments, researchers extracted cells called fibroblasts into culture dishes, allowing them to grow and produce enough cells to experiment with, and then stressed the cells with chemicals that induced them to become senescent. But in living organisms, cells interact with tissues around them, strongly affecting the cells’ gene activity.

This means that the characteristics of cells growing isolated in a glass dish could be quite different from that of cells in their natural environment.

To create a more powerful tool for their studies, postdoctoral scholar Nabora Reyes de Barboza, Ph.D. and colleagues improved on a common technique of fusing a relevant gene—in this case, the p16 gene, which is overly active in senescent cells—with green fluorescent protein (GFP) as a marker that can reveal the location of the cells under ultraviolet light.

By enhancing the quantity and stability of green fluorescent protein in these senescent cells, Reyes greatly amplified the fluorescent signal, finally enabling the researchers to see senescent cells in their natural habitat of living tissues.

“Zombies” stimulate stem cells shortly after birth

Using this highly sensitive tool, the researchers found that senescent cells exist in young and healthy tissues to a greater extent than previously thought, and actually begin appearing shortly after birth. The scientists also identified specific growth factors that senescent cells secrete to stimulate stem cells to grow and repair tissues.

Relevant to aging and tissue injury is the discovery that cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation seen in aged or damaged tissue is a critical modifier of senescent cell activity and regeneration.

In their studies of lung tissue, Peng’s team observed green glowing senescent cells lying next to stem cells on the basement membrane that serves as a barrier preventing foreign cells and harmful chemicals from entering the body and also allows oxygen to diffuse from air in the lungs into underlying tissues. Damage can occur at this dynamic interface.

The team saw senescent cells in similar positions in other barrier organs such as small intestine, colon, and skin, and their experiments confirmed that if senescent cells were killed with senolytics, lung stem cells were not able to properly repair the barrier surface. Leanne Jones, Ph.D., director of the UCSF Bakar Aging Research Institute and Stuart Lindsay Endowed Professor in Experimental Pathology, said Peng’s study is truly significant for the field of aging research, where the goal is to help individuals live longer and more healthy lives.

“The studies suggest that senolytics research should focus on recognizing and precisely targeting harmful senescent cells, perhaps at the earliest signs of disease, while leaving helpful ones intact,” she said. “These findings emphasize the need to develop better drugs and small molecules that will target specific subsets of senescent cells that are implicated in disease rather than in regeneration.”

Additional authors include Nabora Reyes, Maria Krasilnikov, Nancy C. Allen, Jinyoung Lee, Ben Hyams, Minqi Zhou, Supriya Ravishankar, Monica Cassandras, Chaoqun Wang, Imran Khan, Michael Matthay, and Dean Shappard from the Department of Medicine, Pulmonary and Critical Care Division, Peri Matatia and Ari Molofsky from the Department of Laboratory Medicine, Makato Nakanishi of University of Tokyo, and Judith Campisi of the Buck Institute.


Triggers of Senescence
Senescence can be triggered by a variety of stresses including but not limited to telomere shortening, oncogene activation and the presence of reactive oxygen species (Figure 1).

FIGURE 1
Triggers and biomarkers of cellular senescence. There are several stimuli or triggers that activate cellular senescence (red outline). Some of these are depicted in the figure such as the formation of Reactive Oxygen Species (ROS) both from external factors or internal such as mitochondrial dysfunction. Others include the expression of certain oncogenes, e.g., RAS (Rat sarcoma virus) or the loss of tumour suppressor genes, e.g., PTEN (Phosphatase And Tensin Homolog). The shortening of telomeres due to the lack of telomerase enzyme also elicits cellular senescence. Additionally, mitochondrial dysfunction, which can be due to mitochondrial malfunction, increase in mitochondrial size or mass, mitochondrial fusion or mitochondrial fragmentation can also induce senescence. As there is no gold standard biomarker of senescence, a combination of several biomarkers are used to identify this cellular phenotype both in vitro and in vivo. Some of these biomarkers are the release of a senescence-specific secretome, the senescence-associated phenotype (SASP) formed by proteins, vesicles, metabolites. Other biomarkers the presence of DNA damage and the establishment of a stable cell cycle arrest. Furthermore, chromatin alterations such as heterochromatin foci (senescence-associated heterochromatin foci, SAHF) or the presence of chromatin in the cytoplasm (cytoplasmic chromatin fragments, CCF) are also present during senescence. Finally, the most extensively used biomarker of senescence is the presence of senescence-associated -β- galactosidase activity (SA-β-Gal) which is due to an increase in lysosomal activity, although it is important to take into account that this feature is not exclusive of senescent cells.

Telomere Shortening
Telomeres are heterochromatic repeated sequences of nucleotides at both ends of human chromosomes, consisting of 8–12 kilobases at birth. With each DNA replication, 50–200 base pairs of telomeres are lost from each human cell, due to the inability of DNA polymerase to replicate the whole molecule. Telomeres shorten with each cell division until they reach a critical point. As a result, a DNA damage response (DDR) is elicited, which in turn increases p16INK4A and p21CIP1 cellular levels finally promoting senescence (Di Micco et al., 2021). This type of senescence is called replicative senescence because it originates from the number of replications a cell line undergoes (Deng et al., 2008; Fafian-Labora and O’Loghlen, 2020).

Oncogene Activation
Oncogene overexpression and tumour suppressor gene inactivation promote oncogene-induced senescence (OIS). Oncogenes are mutated forms of normal genes present in the human genome, called proto-oncogenes. Under normal circumstances, these genes regulate physiological functions favourable to the cells, but when mutated by gene overexpression or amplification they have the potential to promote cancer development. Tumour suppressor genes code for proteins regulating pathways that contribute to the prevention of cancer development. Thus, their loss of function leads to the loss of these cancer-protective properties, causing cancer. Oncogenes known to be overexpressed in OIS include RAS, BRAF, AKT, E2F1 and cyclin-E. Tumour suppressor genes commonly lost in OIS are PTEN and NF-1 (Gil and Peters, 2006; Perez-Mancera et al., 2014; Lee and Schmitt, 2019).

Mitochondrial Dysfunction
Reactive oxygen species (ROS) is a group of molecules, including hydrogen peroxide (H2O2), superoxide ion (O2 •-) and hydroxyl radical (•OH). They are products of oxidative metabolism in mitochondria, usually scavenged by the enzyme superoxide dismutase (SOD). When mitochondria malfunction, ROS are released causing oxidative damage to mitochondrial and cellular DNA (Desdin-Mico et al., 2020; Di Micco et al., 2021; Martini and Passos, 2022). ROS can also form from the interaction of exogenous factors, such as UV radiation and chemicals from tobacco, and damage cellular DNA. These reactions signal a DDR similar to that caused by telomere shortening, activating p21CIP1 and p16INK4A and causing senescence (Di Micco et al., 2021; Prasanna et al., 2021).

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261318/


More information: Nabora Reyes de Mochel et al, Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung, Science (2022). DOI: 10.1126/science.abf3326www.science.org/doi/10.1126/science.abf3326

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