Blockbuster Review丨The Most Promising Anti-Aging Therapies, How Do I Choose by Class?

Editor's Note

As early as 2020, Professor Brian Kennedy, Singapore's "anti-aging national teacher", worked at Nature Reviews· Drug Discovery published an in-depth review, which summarized and inventoried the most in-depth research and the closest anti-aging substances to clinical application.

Two years later, Professor Kennedy et al. went a step further and explained the specific mechanisms behind these mainstream anti-aging therapies from multiple perspectives such as molecules, cells and systems. I believe that whether it is a novice who lacks a comprehensive understanding of the field of anti-decay, or an old reader who is deeply trapped in the myth of tonic life extension, who does not know how to choose according to needs and by class, reading this article will gain something.

Illustration: Targeted aging mechanisms: a pharmacological perspective

【Molecular level】It can improve the anti-aging mechanism and drugs of reactive oxygen radical aging, protein homeostasis damage, abnormal genomic stability and apparent regulation of aging.

No.1

Prevents oxidation

antioxidant

Respiration is a slow burning. As we age, the body will inevitably be damaged by combustion, producing reactive oxygen species (ROS), leading to the occurrence of chronic inflammation or the accumulation of cell debris, which in turn exacerbates oxidative stress and constitutes a poor positive feedback loop.

Substances that can capture and neutralize ROS are called antioxidants, and are classified as endogenous (the body can produce itself, such as peroxide dismutase, catalase, glutathione, etc.) or exogenous (those that need to be supplemented). However, many studies have shown that the effects of exogenous antioxidants are questionable, and excessive supplementation can even cause the opposite effect.

Modern medical views believe that the best means of antioxidants is not to directly eliminate reactive oxygen species, but to induce the synthesis of endogenous antioxidants by activating the "nuclear factor erythroid 2-related factor 2" (NRF2) signaling pathway. This method can not only exert antioxidant effects more efficiently, but also avoid placing additional burdens on the body.

Deuterated polyunsaturated fatty acids

In addition to eliminating ROS, avoiding oxidative damage is also an effective means. Because ROS attacks lipids containing C-C double bonds, especially polyunsaturated fatty acids (PUFAs), which induce lipid peroxidation. The use of the isotope deuterium of hydrogen atoms to replace the hydrogen atoms on the C-C double bond of the deuterium PUFAs (dPUFAs), can reduce lipid peroxidation, reduce oxidative stress and prolong the life of nematodes, but also alleviate the cognitive impairment of Huntington's disease mice, dPUAFs have entered the clinical test stage.

No.2

Mediates protein homeostasis

Autophagy inducer and proteasome activation factor

Autophagy is the process by which the autophagosomes of cells fuse with lysosomes to degrade intracellular abnormal molecules and old organelles, and is a special catabolic pathway.

Some anti-aging drugs can reduce the accumulation of macromolecules and organelles damaged during aging and age-related diseases by enhancing autophagy, such as Woman penicillin (an inhibitor of PI3 kinase-VPS34), tricostatin A, β hydroxybutyric acid (an inhibitor of histone deacetylase), spermidine (an inhibitor of mitogen-activated protein kinase), rapamycin, everolimus (an inhibitor of the mTOR pathway), and metformin, resveratrol (an agonist of adenylate-activated protein kinases).

In addition to autophagy, some non-specific small molecules, such as p38-MAPK inhibitors, can also extend the effective life of proteins by activating proteasomes.

Anti-glycosylation agent and AGEs crosslinking destroyer

Glycosylation is a very common protein modification, but partial glycation reactions lead to the formation of harmful advanced glycation end products (AGEs).

Several plant-derived phenolic compounds have anti-glycosylation properties that can extend the lifespan of model animals. For example, cobbate can prevent AGE-induced collagen crosslinking and protect cells from oxidative damage; ferulic acid and picotol can extend the lifespan of nematodes; and in one in vitro cell experiment, rosemary and sage acid can reduce the formation of AGEs and reduce the concentration of methylglyoxal and carbonylated proteins by 90 percent.

However, when AGEs are formed, destroyers can also act as blockers, and some thiazole derivatives such as N-benzoylthiazole bromide (PTB) and alacloramine (ALT-711) and pyridine derivatives such as TRC4186 and TRC4149 can break down diketone compounds, thereby breaking down the crosslinking of AGEs.

ECM stimulating factor

The extracellular matrix (ECM) is a complex network structure of glycoproteins and proteoglycans secreted by cells into the extracellular interstitium. Structural proteins in the extracellular matrix are primarily collagen and elastin, which can be assembled in different tissues in different fibrous forms, giving tissue tensor and elasticity respectively [2]. Collagen changes associated with aging can reduce the structural and mechanical integrity of collagen fibers and impair the ability of cells to repair.

Aortic elastin is usually synthesized only early in adolescence, but minoxidil has been shown to stimulate the expression of aortic elastin in adult hypertensive rats.

No.3

Maintain genomic stability

Reverse transcription transposon factor inhibitors

Retro-transposable elements (RTEs) are DNA fragments that code for proteins, which can lead to epigenetic changes and cellular senescence, are a major cause of aging-related genomic instability, and trigger inflammatory antiviral responses.

The type I interferon (IFN-I) response is one of the pathways in senescent cells that helps maintain an "aging-related secretion phenotype." Studies have shown that treating elderly mice with the nucleoside reverse transcriptase inhibitor lamivudine down-regulated the activation of IFN-I and the occurrence of inflammatory responses.

Telomere stabilizer

The shortening of telomeres is closely related to replication senescence and the activity of telomerase. Cellular DNA shortens by one segment with each copy of telomeres, and when shortened to hayflick point, it may initiate a DNA damage detection point, activate p53, cause p21 expression, and lead to irreversible exit of the cell cycle and toward decay.

Studies have shown that supplementation with nicotinamide single nucleotide (NMN) in mice can increase the content of NAD+, thereby stabilizing telomeres and reducing DNA damage, improving liver fibrosis levels in mice.

No.4

Regulatory epigenetics

The eukaryotic cell genome contains two types of genetic information: genetic information in the traditional sense, that is, the genetic information provided by DNA sequences; and epigenetics information, which provides instructions for when, where, and in what way to apply genetic information. At present, the most understood about the regulation of aging by epigenetic mechanisms is the involvement of histone Deacetylase (HDACs) in the regulation of cellular senescence [2].

The Sirtuin protein family is a highly conserved class of HDCs with NAD+ binding domains and catalytic functional domains that can regulate acetylated modification and ADP ribosome modification of multiple proteins, so Sirtuin's activators are also listed as potential anti-aging drugs, but their effect is still controversial. In contrast to Sirtuin, reducing the expression of Rpd3 (the homologous gene for HDAC1) can extend the lifespan of yeast, worms, and fruit flies. Therefore, inhibitors of Rpd3 are more likely to become potential anti-aging molecules.

In a human clinical anti-aging study based on an "epigenetic clock": the experimental group reduced the physiological age by about 2.5 years after 12 months of combined treatment with recombinant human growth hormone (rhGH), dehydroepiandrosterone (DHEA) and metformin compared with the control group.

【Cellular level】To cope with aging at the cellular level, you can start with mitochondria first, followed by the stress response and cleansing methods of cells.

No.5

Regulates mitochondrial function

Mitochondrial low toxicity stimulants

Mitohormesis refers to low doses of non-cytotoxic ROS that stimulates mitochondria to make activities conducive to cell survival and development, such as increasing the expression level of endogenous antioxidants and performing mitochondrial autophagy within a controllable range. However, when ROS exceeds a certain concentration, it will cause irreversible damage to mitochondria and cells.

Metformin can partially inhibit complex I in the respiratory response chain, hindering electron transport and producing ROS in a controllable dose range. In light of this, the first clinical trial to evaluate drug methods to delay debilitation, TAME (Target Aging with Metformin), has been initiated. However, the use of metformin in non-diabetic patients to fight aging is still controversial.

Mitochondrial autophagy promoter

Mitochondria are one of the most important organelles within the cell, and mitochondrial dysfunction can lead to various aging diseases such as sarcopenia and weakness, as well as Alzheimer's and Parkinson's disease. Mitophagy is the targeted phagocytosis and destruction of mitochondria by autophagy devices, which can prevent the accumulation of damaged mitochondria.

Urisin A is a natural metabolite produced by the intestinal microbiota acting on ellagic acid, which promotes mitochondrial autophagy in older animals and improves muscle health. The first clinical trials of urethane A showed that a 4-week treatment of urea lithollis A altered the expression of mitochondrial genes in skeletal muscles in sedentary populations and regulated the content of acyl carnitine in plasma.

Prevents NAD+ losses

Nicotinamide adenine dinucleotide (NAD+), an important coenzyme in the human body, plays a unique role in DNA repair and epigenetic mechanisms that are closely related to aging.

Nicotinamide ribose (NR) is a NAD+ precursor. Intake of NR can increase whole blood NAD+ levels without significant side effects. Like NR, another precursor to NAD+, nicotinamide mononucleotide (NMN), can restore cerebrovascular endothelial function in old mice and rats, improving cognitive function.

No.6

Low toxicity stimulant

High dose toxicogenic factors are harmful to organisms, while low dose toxicogenic factors are beneficial to organisms. Through the micro-interference of low-dose poisons on homeostasis in the body, a series of repair and maintenance mechanisms are initiated to increase the expression of cell protection and repair proteins, which is the basic principle of low toxic excitatory effect (hormesis) to prevent aging. The aforementioned mitochondrial low toxicity excitatory effect is also one example.

Many natural compounds, such as polyphenols, isothiocyanates, terpenes, and polyamines in small doses, activate stress factors such as FOXO3a, heat shock transcription factor 1 (HSF-1), AMPK, or NRF2 for anti-aging and life-prolonging effects.

The study found that sulforaphane, derived from broccoli, was able to activate the NRF2 signaling pathway and extend the lifespan of nematodes by 18.2%.

No.7

Remove senescent cells

Senolytics

Senolytics, literally translated as "senescent cell cleavers," are a class of drugs that target the removal of senescent cells from the body. Dozens of candidate compounds have been shown to be effective in humans, such as dasatinib and quercetin.

Senostatics

Senostatics are a more gentle class of anti-aging drugs used to prevent excessive damage caused by the accumulation of senescent cells. Initial therapeutic targets for some Senostatics have been identified, such as NF-κB, p38, GATA4, mTOR, BRD4, and cGAS/STING.

【System level】Jump out of molecules and cells, and elaborate methods for intervening in aging from the system level.

No.8

Treatment of aging-related diseases

Antifibrotic drugs

Fibrosis (fibrosis) can occur in a variety of organs, the main pathological changes are increased in the fibrous connective tissue in the organ tissue, parenchymal cells are reduced, and continuous progression can lead to organ structure destruction and function loss, and even failure.

Preclinical studies have shown that pirfenidone and nidanibu can treat idiopathic pulmonary interstitial fibrosis (IPF), and L-carnitine and rhubarb extracts have also been shown to slow tubular interstitial fibrosis (TIF).

Immunomodulators

Some potential anti-aging drugs have well-defined immunomodulatory properties. Lithium can affect all aspects of the immune system, including the activity of B, T cells, and macrophages, as well as cytokine levels; NAD precursors can alleviate dysfunction of mitochondria in T cells; metformin can delay aging-related inflammation; and acarbose selectively regulates the gut microbiome to improve immune system function in patients with early diabetes.

No.9

Regulates the intestinal flora

The gut microbiota plays an important role in the maturation, function, and regulation of the host immune system, which co-evolves a mutually beneficial relationship with trillions of beneficial microbes in our bodies while responding effectively to invading pathogens.

Some colonic bacteria produce substances with potential anti-aging properties, such as urethropoietin A, spermidine, vitamin K2, and short-chain fatty acids (SCFAs).

【Multiple effects】Summarize the signaling pathways related to aging.

No.10

Suppression or activation of signal paths

Senescence is a physiological response of normal cells to a series of stressful stimuli that can be induced by a variety of cellular signaling pathways. These aging-related signaling pathways often overlap, and if their interventions are combined, they may have a superimposed or synergistic effect.

Scholars have summarized the interventions (activation or inhibition) corresponding to these signaling pathways:

TORC1 inhibitors; PI3K inhibitors; Ras inhibitors; Myc inhibitors; AT1 inhibitors;

Sirtuins Activator; AMPK Activator; Klotho Activator.

—— TIMEPIE ——

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