influence of senolytics and senomorphics on immune metabolic processes

Aging is a natural physiological process, but its onset earlier than expected can be a serious problem. The onset of cellular aging often precedes chronological aging, which is associated with the body's loss of ability to regenerate and cellular senescence. These factors play a very important role in premature aging.

There are different ways to combat senescent cells, including drugs (treatment with drugs such as rapamycin, dasatinib, metformin) and non-drug methods (special diets and dietary supplements). Clinical data on pharmacotherapy with senotherapeutic drugs are quite scarce, and short-term and long-term side effects have not been studied, so the second option is preferable in this case. But is it possible to delay aging with the help of special products and dietary supplements? Let's figure it out.

What is senescence and why does it happen?

On Wikipedia It is written that “cellular senescence, or senescence, is a stress-induced irreversible arrest of the cell cycle of somatic cells capable of proliferation.” In simple words – replicative cell aging. That is, those cells that have reached their limit in the number of cell divisions (Hayflick limit), stop dividing. Typically, such “old” cells self-destruct, that is, they go into apoptosis (programmed cell death) and die quietly and “cleanly”, without causing much harm to the body. Senescence mediates phenotypic changes in cells. Such cells are not able to divide, but are not ready to go into apoptosis. Due to the inability to “die in peace,” they begin to secrete various inflammatory factors, attracting immune system cells. This set of inflammatory factors has a special name – SASP (senescence-associated secretory phenotype). Thus, senescence is one of the causes of inflamma- tion or inflammatory aging, which develops through autocrine and paracrine changes in physiological reactions in the microenvironment through SASP.

A little theory and molecular mechanisms.

SASP components include various biological molecules: growth factors (IGFBPs, EGF), cytokines (IL-6, IL-1β, TNFa), chemokines (IL-8, MCP-2), proteases (MMPs) and extracellular matrix components ( collagens, fibronectin, laminin). Some of them are permanent components of SASP and are used as markers (IL-6 and IL-8).

Special protein markers of senescence:

The P16 INK4A protein is a tumor suppressor that slows down cell division, suppressing the proliferation of cancer cells. Its expression on the cell surface is a biological marker of oncology.

The p53 protein is a regulatory protein that is associated with DNA damage and cell cycle arrest. A mutation in it often mediates the onset of carcinogenesis.

The p21CIP1 protein is the main target of p53 protein activity and plays an important role in regeneration.

The most abundant transcript in senescent cells is the long noncoding RNA (lncRNA) PURPL, a regulator of p53 levels.

One of the main mechanisms leading to the formation of the SASP phenotype is the activation of the nuclear factor NF-kB. In senescent cells it is constitutively activated, leading to increased production of proinflammatory cytokines, chemokines, proteases, growth factors and other substances.

The influence of nutrition on immune metabolism.

Immune metabolism is a type of cellular metabolism that influences the functions of the immune system and contributes to the metabolic reprogramming of the immune response. The cell’s ability to activate and proliferate depends on this.

Depending on the situation, immune cells adopt a variety of metabolic strategies to maintain energy balance, biosynthesis, and their lifespan. For example, cells in a resting state are more likely to use oxidative phosphorylation to meet basic energy and survival needs. And during activation of the immune response, cells switch to glycolysis, which promotes active proliferation, production of inflammatory cytokines and adaptation to hypoxia.

Senescent cells, compared to normal cells, have increased glycolyticity, which contributes to the formation of the SASP phenotype. The accumulation of such cells in tissues leads to metabolic imbalance. Activation of glycolytic pathways entails changes in pH levels, redox homeostasis, and metabolite concentrations. This negatively affects the immune response. Dysregulation occurs: both dysfunctional and hyperactive immune cells appear.

Nutrition is one way to modulate immune cell metabolism. By regulating metabolism through nutrition, it is possible to restore balance in the functioning of immune cells and thus reduce the signs of aging associated with senescence and inflammation.

Many strategies exist to modulate metabolism in immune cells. Here are some of them:

Adding vitamin E and zinc to food improves immunological responses. These nutrients perform their functions by reducing oxidative stress.

Protective effects of the Mediterranean diet on immune function. The foods included in this diet (such as fatty fish and olive oil) contain high levels of polyunsaturated fatty acids, especially omega-3s. These fatty acids help reduce levels of cell adhesion molecules such as ICAM-1 and VCAM-1, as well as inflammatory cytokines such as C-reactive protein and IL-6.

Reducing calorie intake has a beneficial effect on the immune response. There is a decrease in the level of pro-inflammatory cytokines: IL-1β, IL-6 and TNF-α.

Using Probiotics. With the normal functioning of the microbiota, and the absence of inflammatory triggers in the form of the proliferation of opportunistic flora, a decrease in pro-inflammatory cytokines occurs.

Use of senotherapeutic agents. Senescent cells and SASPs can be considered targets for strategies aimed at preventing premature aging. These strategies may include either elimination of senescent cells or selective inhibition of SASP using natural (eg, flavonoids) or synthetic compounds.

Senotherapeutic agents.

Senotherapeutic drugs are a class of medications and natural products that prevent the process of premature aging. They are divided into senolytics and senomorphics.

Senolytics are small molecules that cause the death of senescent cells by inducing apoptosis. According to the results research, even a small decrease in the number of these cells significantly reduces the number of age-associated symptoms. The functional status of patients improves.

Senolytics include:

Broad-spectrum kinase inhibitors (dasatinib);

Dietary senolytics of plant origin (flavonoids): quercetin, fisetin, piperlongumin and curcumin;

Inhibitors of anti-apoptotic proteins of the Bcl-2 family (navitoclax);

Combination of drugs. One of the first drugs with a proven senolytic effect was the combination of dasatinib and quercetin. Dasatinib is an antitumor drug, quercetin is a flavonoid. Moreover, it has been proven that their combination exhibits a more powerful senolytic effect than each drug individually.

Currently, dasatinib and quercetin are approved by the FDA. They are effective in eliminating different types of senescent cells. This same drug combination improved functional status and increased lifespan in animal models.

Quercetin – plant flavonoid, acts mainly through mTOR, NF-κB, PI3k/Akt, p53/p21/serpine.

Senolytic properties fisetina are caused by the regulation of NF-κB and Nrf2 (negative regulator of NF-κB).

Piperlongumine — natural alkaloid amide. Induces apoptosis of senescent cells in a ROS-independent manner.

Curcumin exerts its senolytic activity through activation of Nrf2, decreased activation of NF-κB, and decreased expression of proinflammatory cytokines. This is accompanied by a decrease in the levels of IL-1β and TNF-α and an increase in the level of IL-10.

Senomorphics are small molecules that help block SASP without cell death, which also prevents aging. Their targets are pathways associated with SASP expression: p38MAPK, PI3k/Akt, mTOR and JAK/STAT. And transcription factors such as NF-κB, C/EBP β and STAT3.

Senomorphics include:

NF-kB inhibitors (kaempferol, apigenin);

mTOR inhibitors (rapamycin);

Activators of AMP-dependent kinase (metformin);

Autophagy stimulators (resveratrol, epigallocatechin-3-gallate (EGCG)).

Dietary plant-derived senomorphics (flavonoids) are: resveratrol, kaempferol, apigenin, and EGCG.

Senomorphic properties resveratrol consist of inhibition of the NF-κB pathway and activation of the transcription factor Nrf2. It has the ability to increase mitochondrial activity and the associated oxidative phosphorylation pathway.

Apigenin And kaempferol suppress NF-κB activity through the IRAK1/IκBα signaling pathway.

EGCG (epigallocatechin-3-gallate) may suppress aging through inhibition of stress-induced PI3k/Akt/mTOR signaling and inhibition of AMPK activation. May also inhibit the expression of ROS, Cox2, NF-κB and SASP factors (IL-6 and TNF-α) as part of its antioxidant activity.

It turns out that if you include foods rich in flavonoids in your daily diet, then in theory, you can influence immune metabolism and, thus, neutralize some of the senescent cells in an absolutely safe way. The main thing is to start doing it all on time. After all, the fewer senescent cells we have, the further away old age is from us. Do you agree? Or is it all too simple, and here, like everywhere else, there are pitfalls? Your opinion?