In the longevity medicine field, one of the spotlights is being cast on cells that reach an important stage in life, specifically, senescent cells. When cells are stressed, depending on the cell, type of stressor and intensity of the stimulus, they can respond by inducing repair processes, inducing cell death, or inducing senescence. These senescent cells are cells that have entered a state of permanent arrest in the cell cycle, no longer dividing but remaining metabolically active. They are a double-edged sword in the biological process. On one hand, they play a crucial role in wound healing and embryonic development. On the other hand, their accumulation is linked to aging and a host of age-related diseases. This article aims to delve deeper into the complex world of senescent cells and the senescence-associated secretory phenotype (SASP), shedding light on their role in aging and the potential they hold in the field of longevity medicine.
What are senescent cells and cellular senescence?
Cellular senescence is a state of permanent cell cycle arrest that normal cells undergo when they sustain damage. Despite their non-dividing status, senescent cells are metabolically active, resistant to apoptosis, and secrete a variety of bioactive molecules, a phenomenon known as the senescence-associated secretory phenotype (SASP). Furthermore, when senescence influences stem cells, it hampers the capacity of tissues to repair and regenerate, thereby adversely affecting tissue homeostasis. Senescence can be triggered by a variety of factors, including telomere erosion, oxidative damage, and oncogene activation.
During fetal development or following acute injury with cell and tissue damage, transient senescence and SASP promote tissue remodeling, induce immune response, and induce clearance of senescent cells, benefiting the organism. Moreover, senescence serves as an early barrier against cancer by preventing the propagation of damaged DNA; however, senescence can also contribute to aging and disease. Senescent cells accumulate in tissues over time, promoting chronic inflammation and impairing tissue homeostasis, causing cell, tissue and organ dysfunctions which ultimately lead to aging and the development of age-related diseases.
What is the senescence-associated secretory phenotype (SASP)?
Most cells undergoing senescence are going to develop a senescence-associated secretory phenotype. SASP release pro-inflammatory, pro-apoptotic and pro-fibrotic factors both in a paracrine and endocrine fashion, influencing both nearby cells and distant ones to become senescent. As long as the NK cells and other immune cells are capable of clearing senescent cells, which usually happens within a couple of days to a couple of weeks, no negative effects occur. Once a threshold is hit, the generation of senescent cells outpaces their clearance, causing them to start to accumulate and leading to several dysfunctions. Inflammaging, tissue fibrosis and extracellular matrix (ECM) degradation, insulin resistance, stem cell exhaustion with impaired regenerative abilities for tissues, impaired muscle hypertrophy in response to resistance training, promotion of malignancies development are some of the effects associated with SASP.
Different cell types and tissues, different causes of senescence, different intracellular and extracellular environments, and different time points may show a wide range of different factors being secreted by SASP cells.
The SASP secretes various types of molecules including:
- Cytokines: These are small proteins that are crucial in cell signaling. They are released by cells and affect the behavior of other cells. Cytokines secreted by SASP include IL-6 and TNF-alpha.
- Chemokines: These are a type of cytokine with the ability to induce directed chemotaxis in nearby responsive cells. Chemokines secreted by SASP include CXCL1 and CXCL2
- Growth Factors: These are substances which are required for the stimulation of growth in living cells. Growth factors secreted by SASP include EGF, IGF and VEGF
- Proteases: These are enzymes that perform proteolysis, i.e., they break down proteins and peptides. Proteases secreted by SASP include MMP3 and MMP9
- ECM Components: These are the components of the extracellular matrix, a collection of extracellular molecules secreted by cells that provides structural and biochemical support to the surrounding cells. ECM components secreted by SASP include collagen and elastin.
- Other Factors: This includes a variety of other molecules that are secreted by the SASP. Among the many molecules there are reactive oxygen species (ROS) and reactive nitrogen species (NOS).
What causes cells to become senescent?
Any damage, stressor or acute injury can result in senescence. Among the many triggers of cellular senescence there are:
- Telomere Erosion: The gradual shortening of telomeres, the protective caps at the ends of chromosomes, can lead to cell senescence.
- Oxidative Damage: Oxidative stress, caused by an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to counteract their harmful effects, can induce cell senescence.
- DNA Damage: DNA damage can occur for a variety of reasons, including telomere erosion and oxidative damage.
- mtDNA Damage: mitochondrial DNA damage can occur for a variety of reasons, including ROS
- Metabolism Dysfunctions: Abnormalities in cellular metabolism can trigger cell senescence, including mitochondrial dysfunction.
- Cytokines: These small proteins are crucial in cell signaling and can induce cell senescence.
- Oncogene Activation: The activation of oncogenes, genes that have the potential to cause cancer, can lead to cell senescence.
- Chemotherapy Agents: Certain drugs used in chemotherapy can induce cell senescence.
- Replicative Stress: Stress induced by repeated cell division can lead to faster telomere shortening and cell senescence.
- Ionizing radiations: X-Rays, Gamma Rays, UVs
- Reactive metabolites: besides Reactive Oxygen Species (ROS), also Reactive Nitrogen Species (NOS) can trigger senescence.
- Viral infections: as a way to block viral replication, cells may enter senescence in response to infection.
Role of senescent cells in aging and disease
There is currently no sensitive and specific biomarker of senescent cells, but by combining several biomarkers we can manage to link disease, senescence and interventions targeting senescence.
While senescent cells may be present even at the earliest stage of human life, like the blastocyst stage in response to hypoxia, most young individuals (up to 20-30 years old) have undetectable levels of senescent cells in tissues. However, when testing older adults (40-80 years old) 5% or more of cells are senescent.
From studies in animals, we know that by transplanting few senescent cells in a healthy tissue like a joint, that is enough to cause age-related osteoarthritis. By transplanting senescent cells intraperitoneally, we’ve seen onset of frailty and age related diseases and premature death, which does not happen when transplanting non-senescent cells. These effects occur when as little as 1 in 10,000 cells is senescent. In older or obese animals, signs of frailty, early aging, and increased mortality can be observed even when only half the number of cells typically required for lean, middle-aged mice are transplanted.
Senescent cell accumulation has been observed in a wide range of age-related conditions including:
- Frailty and impaired deambulation in the elderly
- progeroid syndromes in children
- macular degeneration
- several skin conditions including impaired wound healing
- pulmonary fibrosis
- heart disease
- kidney disease
- liver disease
- type 2 diabetes mellitus
- and many more…
What can longevity medicine do to tackle senescent cells?
As we saw in previous paragraphs, senescent cells have an important and protective role in human physiology since the earliest stages of development. For this reason, trying to find a way to eliminate senescence completely, by reducing the expression of p53 for example, would not be a good idea and would likely increase risk of cancer. However, facilitating the removal of senescent cells once they are already formed and inducing the clearance of SASP might decrease cancer risk, the spread of senescence, tissue dysfunctions and delay aging and the development of age-related diseases.
There are several bioactive molecules being actively investigated which are effective in reducing the burden and even reverse damage caused by senescent cells.
Currently, two different types of senotherapeutics are being investigated:
- Senolytics, which are molecules that selectively eliminate senescent cells.
- Senomorphics (aka SASP inhibitors), which are molecules that decrease or inhibit SASP.
Among the senolytics being studied there are the combination of dasatinib and quercetin (D+Q), and fisetin, while among the senomorphics there are the notorious rapamycin and other rapalogs like everolimus. I’ll get into the details on senotherapeutics in a dedicated blog article.
- Mechanisms and Regulation of Cellular Senescence.
L Roger – International Journal of Molecular Science, Dec 2021
- Cellular senescence and senolytics: the path to the clinic.
S Chaib – Nature Medicine, Aug 2022
- The role of cellular senescence in ageing and endocrine disease.
S Khoslo – Nature Reviews Endocrinology, May 2020