Reducing Senescent Cell Burden in Aging and Disease

Cellular senescence accumulation is closely associated with a wide array of diseases and disorders typically linked to aging – diseases such as Alzheimers, Cancer, Parkinsons, and more. The clinical use of senolytic compounds is hypothesized, with strong evidence, to reduce your chances of senescent cell (SC) accumulation.

Cellular senescence accumulation is closely associated with a wide array of diseases and disorders typically linked to aging -- diseases such as Alzheimers, Cancer, Parkinsons, and more. The clinical use of senolytic compounds is hypothesized, with strong evidence, to reduce your chances of senescent cell (SC) accumulation. Reduction of cell senescence is key to lowering your likelihood of suffering from various age related diseases.

What is cellular 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 cellular senescence?

Cellular 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.

Apoptosis, also known as “cell death,” is the conditioned way our cells are programmed to kill damaged cells. When we’re young and healthy, it’s easy for our body to work in autopilot recycling out any cells that are damaged.

When a cell isn’t naturally killed off by apoptosis, it enters a state of senescence where it is not allowed to replicate or grow. Senescent cells are often referred to as “zombie-like” cells because although they can’t grow, they can take over healthy cells and turn them into a senescent state.

How do you reduce cellular senescence?

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

7 Ways Cellular Senescence Is Induced on a Genetic Level

These seven inducers cause a cell to express the senescent cell 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 senescent cell phenotype is characterized with irreversible arrest of cell growth, SASP production, resistance to apoptosis, persistent DNA damage, and epigenetic structural changes.

1. 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.

2. 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.

3. 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.

4. 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.

5. Mitogens

Mitogens are non-specific stimulants of the cellular cycle and induce mitotic cell division.

6. 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.

7. 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.

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 are senolytics used to reduce senescent cell burden?

Senescent cells 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 are derived from the treatments of cancer. Evidence also suggests that the use of different combinations of senolytics will have a greater effect clearing senescent cells -- both a larger volume and larger variety.

The frequency of senescent cell re-accumulation or “turnover” is estimated at four weeks. This time table allows for intermittent treatment with senolytics, reducing possible side effects from the senolytics.

Now, results from clinical studies also provide evidence that senolytics 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 senescent cells don't replicate and replication is the driving factor behind drug resistance.

Even if your body can properly deal with the presence of senescent cells, senolytics have been shown to have a boosting effect on the immune system. The use of SASP-inhibitors does not clear senescent cells, but it does reduce the strain, with inhibition very similar to the elimination of senescence genetically and pharmacologically.

Accessing Senolytics

In summary, senescent cell burden has been extensively studied both in pharmacological and genetic settings with both having strong and compelling evidence that senolytics 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.

Healthspan is the first online medical clinic that is dedicated to fighting age-related disease through senolytic interventions. In just 15-20 minutes, you can complete our online intake form to have a functional medicine physician review your intake and receive a senolytic prescription.

Click here to start your online evaluation.

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