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Related Protocols

Rapamycin

The most powerful tool to stop the acceleration of aging caused by mTOR dysfunction and cellular senescence.

Reducing Senescent Cell Burden in Aging and Disease

We'll be covering how you can reduce senescent cell burden with respect to aging and disease.

Cellular Senescence

6 mins

By: Daniel Tawfik

Brief:

Cellular senescence accumulation is closely associated with a wide array of diseases and disorders typically linked to aging, diseases such as alzheimers.

The clinical use of senotherapeutic compounds is hypothesized, with strong evidence, to reduce your chances of senescent cell (SC) accumulation. Senotherapeutics can be broken down into two classes, senomorphics and senolytics

Reduction of cell senescence is key to lowering your likelihood of suffering from various age related diseases.

What is cell senescence?

Cellular senescence is a hallmark for the aging processes of a cell and is a state in which cellular resistance to apoptosis is higher, the production of senescence-associated secretory phenotype (SASP) is taking place, mitochondrial dysfunction occurs, as well as changes within the cell's DNA and its supporting molecules. It is quite efficient at stopping the growth of tumors, however the cell remains alive in a non-functional, static state.

What causes cell senescence?

Senescence is caused by stress and developmental signals. A cell has three ways of dealing with stress; repair, apoptosis, and senescence. The decision of which option the cell takes is dependent on the degree of stress the cell receives.

How do you Reduce Cellular Senescence?

You can reduce the level of senescent cells via the intermittent use of available senotherpeutics agents to essentially supress or clean out and remove these static cells. Additionally the use of SASP inhibitors and/or other SASP modulators will reduce the burden of SC’s but need to be taken on a more regular schedule than senolytic agents.

Cellular Senescence on a Genetic Level.

Cell Senescence is commonly induced via

damage to DNA
- When DNA is damaged a DDR or DNA damage response is induced. DDR induction is commonly caused by damage to telomic structures via the shortening of telomeres, dysfunction of telomeres, as well as mutations, radiation damage, and alkylating agents.
reactive metabolites
- Reactive metabolites are molecules that are commonly electron deficient molecules which cause them to “react” to other non-reactive molecules(enzymes, receptors, cell membranes, and DNA) by forming a covalent bond with them. This reaction causes changes to the protein's structure or the DNA’s structure.
- A protein's structure determines a protein's function. When misfolded proteins are detected by the cell via antigens, an immune response is induced.
- DNA structure is directly correlated to gene expression, so any changes to your DNA’s structure can lead to various cellular problems.
inflammation
- Cellular inflammation is the increased activity of the gene transcriptor, Nuclear Factor-KappaB (NF-kB).
- NF-kB is found in every cell and is heavily modulated by essential fatty acids.
oncogenes
- These genes were once beneficial to the cell via regulation of cell growth but have undergone mutation which causes them to turn into oncogenes which can cause uncontrolled cellular growth which can lead to the proliferation of cancerous cells.
- These mutational genes can be inherited from your parents or can be caused by exposure to cancer causing compounds.
mitogens
- Mitogens are non-specific stimulants of the cellular cycle and induce mitotic cell division.
proteotoxic stress
- Proteotoxic stress is caused by protein aggregation, unfolded protein responses, and the activation of the mTOR pathway.
- Proteotoxic stress can lead to the loss of proteostasis, which is the loss of protein regulation within a cell.
- Proteostasis is your cell's way of influencing the life cycle of a protein from synthesis to degradation.
damage-associated molecular patterns (DAMPs)
- These molecules are released from dying and damaged cells due to pathogenic activity and act as an early warning to surrounding cells.
- DAMPs promote the inflammatory response commonly associated with cell senescence and are biomarkers for cell death and dysfunction.

These inducers cause a cell to express the SC phenotype via activation of p16INK4a/Rb and/or p53/p21 which is determined via the types of inducers and the types of cells affected. The SC phenotype is characterized with irreversible arrest of cell growth, SASP production, resistance to apoptosis, persistent DNA damage, and epigenetic structural changes.

What is the senescence-associated secretory phenotype?

The SASP is a phenotype that is characterized by pro-inflammatory cytokines, chemokines, and extracellular matrix-degrading proteins that can induce senescence in normal healthy cells. Now the specific make-up of the SASP is highly dependent on the type of cell affected, what induced that cell to enter senescence, the surrounding environmental factors, and how that particular cell dealt with suppression.

How the use of Senotherapeutics reduce senescent cell burden

Now, SC's are essentially non-dividing cancer cells but have the same metabolic changes as dividing cancer cells. Sounds terrible, right? Well it's not surprising that many senolytics and senomorphics are derived from the treatments of cancer. Evidence also suggests that the use of different combinations of senotherpeutics will have a greater effect clearing SC’s, that is a larger amount of SC’s cleared and a larger variety of SC’s cleared. The frequency of SC re-accumulation or “turnover” is estimated at four weeks. This time table allows for intermittent treatment with senotherapeutics, reducing possible side effects from their use. Now, results from clinical studies also provide evidence that senotherapeutics have minimal adverse effects on humans. Additionally if you're worried about drug resistance build-up, be at ease. The possibility of drug resistance is unlikely due to the fact that SC’s don't replicate and replication is the driving factor behind drug resistance. Even if your body can properly deal with the presence of SC’s, senotherapeutics have been shown to have a boosting effect on the immune system with regards to the clearance of SC’s. The use of SASP-inhibitors does not clear SC’s but it does reduce the strain of SC, with inhibition very similar to the elimination of SC’s genetically and pharmacologically.

In summary, Senescent cell burden has been extensively studied both in pharmacological and genetic settings with both having strong and compelling evidence that senotherapeutics like rapamycin reduce your chances of age related diseases via the clearance of senescent cells. Additionally the SASP can be subject to modification via the use of glucocorticoids, rapamycin, metformin, reverse transcriptase inhibitors or JAK1/2 inhibitors.

The use of senotherapeutics like rapamycin is integral to live a longer healthier life. What is stopping you from improving your own Healthspan?

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