Why it is important to learn about Senescence-associated secretory phenotype (SASP) proteins

Cells can reach their end-game in a number of ways. One way is through terminal differentiation. Terminally differentiated cells, such as neurons and muscle cells, can no longer divide and function as specialized cells.

Another way cells reach their end-game is through programmed death, also known as apoptosis. Apoptotic cells disintegrate into pieces and are taken up by scavenger cells in the body.

A third way cells reach their end-game is through senescence. Senescent cells also can no longer divide, but they remain alive and active for some time. Senescent cells secrete a biochemical soup of proteins into the surrounding extracellular environment. This soup contains pro-inflammatory elements as well as growth modulators and enzymes.

Not all the factors secreted by senescent cells have negative effects. Some of these factors allow for wound healing, reorganization of tissues during development, and cancer cell suppression. Additionally, many of these proteins are part of the arsenal of inflammatory cells in their regulatory role against infections.

Senescence-associated secretory phenotype (SASP) proteins are released by senescent cells. While these proteins can have beneficial effects, such as wound healing and cancer suppression, they can also have damaging effects if they are overproduced.

For example, SASP proteins can promote inflammation. In this context, older individuals often display chronic low-grade inflammatory states with elevated production of pro-inflammatory proteins. This can lead to a number of age-related diseases, such as visceral obesity, frailty, osteoporosis, atherosclerosis, dementia, and cancer (3, 4).

The Role of Exercise in Reducing SASP Proteins

Fortunately, exercise training modifies the pro-inflammatory cascade of aging. Moderate regular physical activity is associated with reduced levels of IL-6 as well as other pro-inflammatory cytokines (4).

A major reason that SASP proteins are reduced with physical exercise could be due to a reduction in visceral adipose cells. Fat cells are an important source of pro-inflammatory factors. Thus, decreasing pathological aging is possible with regular physical exercise supported by a small level of calorie moderation (which also reduces adipose cells).

SASP proteins have far-reaching effects. Unfortunately, as noted above, having senescent cells in an organ generates SASP factors. These have a negative bystander effect on the neighboring cells in the tissue because senescent cells beget senescence in cells in their vicinity.

There are three additional elements that are important to note with regards to the bystander effect of SASP proteins.

SASP proteins induce a DNA damage response

Some SASP proteins, such as IL-6 and IL-8, can induce the DNA damage response (DDR). This can be beneficial in some cases, such as when cells are damaged by cancer treatments. However, it can also be detrimental, as it can lead to cell death or cancer.

Other SASP proteins, such as CTGF and MMP3, do not trigger cells to activate the DNA damage response. In general, SASP proteins that do not induce the DDR are less detrimental than SASP proteins that do induce the DDR. This is because they are less likely to lead to cell death or cancer.

SASP Proteins have local and systemic effects

SASP proteins can have both local and systemic negative pro-inflammatory effects. As noted, locally, SASP proteins can promote inflammation by stimulating the production of pro-inflammatory cytokines, such as IL-6 and IL-8. These cytokines attract immune cells to the site of inflammation, which can exacerbate tissue damage. 

Systemically, SASP proteins can promote inflammation by increasing the expression of pro-inflammatory genes in the liver and other organs. This can lead to a chronic state of inflammation, which - as noted above - is associated with a number of diseases, including cancer, heart disease, and Alzheimer's disease.

SASP proteins create a vicious cycle of a pro-inflammatory state

Aging produces dysfunction of the immune system. This results in ineffectual removal of senescent cells, leading to perpetuation of a chronic inflammatory state.  The ongoing pro-inflammatory state promotes an increase in adipose cells, the development of frailty and loss of muscle mass, and the accentuation of atherosclerosis. Multiple dysfunctional organ systems encourage the release of reactive oxygen species (ROS) which compound senescence, and thus the release of the SASP factors in tissues.

The excess SASP proteins add fuel to the fire by inviting the infiltration of immune cells into the aging tissues. This exacerbates the pro-inflammatory state.

In general,  inducing SASP protein secretion seems to have more negative than positive results, particularly when the secretion is chronic and from senescent cells (as opposed to an acute stress response or from healthy cells as happens during exercise) (4, 5).

As noted, SASP proteins have a beneficial side to them, in terms of fighting infection, producing a positive acute stress response, and curbing cancer cells. However, having senescent cells hang out in tissues seems detrimental, leading to chronic age-related disease and/or autoimmune disease (5, 6).

Research is ongoing in the field of senotherapy, where therapeutics are used to kill senescent cells (senolytics) or modify/block their action (senomorphics). For example, here are several therapies that modulate the effect of SASP proteins (6, 7, 8): 

• IL-6 inhibitors are currently being used in the treatment of rheumatoid arthritis and severe COVID-19 disease (for example, Tocilizumab)
• Rapamycin is an FDA-approved immune suppressant that has been shown to have senomorphic effects in both animal and human studies. It works by inhibiting the mTOR pathway, which is involved in the regulation of cell growth and senescence.
• Metformin: This is an FDA-approved diabetes drug that has also been shown to have senomorphic effects. It works by inhibiting SASP factors and reducing ROS (reactive oxygen species), which can damage cells and promote senescence.
• Resveratrol: This is a naturally occurring compound found in grapes, red wine, and other foods. It has been shown to have senomorphic effects in both animal and human studies. It works by activating the SIRT1 pathway, which is involved in the regulation of cellular aging.
• TGFβ receptor 1 (TGFβR1) inhibition in acetaminophen poisoning improved mouse survival, even when delivered after the therapeutic window. TGFβR1 inhibition reduced senescence and enhanced liver regeneration 

Senescent cells are old, damaged cells that have stopped dividing. They accumulate over time and can contribute to age-related diseases. They do this primarily by secreting Senescence-associated Secretory Phenotype (SASP) proteins. SASP factors have far-reaching effects. Unfortunately, while SASP proteins have critical beneficial effects in acute stress reactions, tumor-suppression, and infection, they also have a negative bystander effect on cells in the tissue, promoting senescence in neighboring cells.

Aging increases the number of senescent cells in tissues and predisposes to the development of  a chronic inflammatory state leading to age-related chronic disease.  Senotherapy is a promising new field of research that has the potential to revolutionize the way we treat age-related diseases. By targeting senescent cells and the SASP factors, we may be able to slow down the aging process and improve quality of life for people of all ages.

1. Proteins of aging and their localization in the cell: Dysfunctional or hyper-functional membrane proteins that induce aging often reside in the basolateral regions of the cellular membrane.
2. Why it is important to learn about Senescence-associated secretory phenotype (SASP) proteins (this article): Senescent cells accumulate over time and contribute to age-related diseases. They do this primarily by secreting Senescence-associated Secretory Phenotype (SASP) proteins. 
3. Senescent cells display unhealthy acidification of the cytoplasm: There are multiple pathways all cascading to generate increased in cytoplasmic acid. These create a positive feedback loop that sets the cell up for a vicious cycle of dysfunctional intracellular organelles and ongoing  intracellular acidosis.
4. An unusual attribute of senescence-inducing factors: Pro-inflammatory factors tend to have more acidic isoelectric point, with more acidic side groups. The evidence suggests that there is a correlation between acidic side-groups, isoelectric point, and senescence-inducing factors.

* Note: not all SASP factors are amino acid based; some are RNA- based. Given that the most well-studied SASP factors are peptide-based, the article refers to SASP proteins (back).