Cellular senescence, characterized by irreversible cell cycle arrest, plays a pivotal role in ageing and the development of age-related pathologies. Mitigating oxidative stress, a primary contributor to cellular ageing, is crucial for inhibiting the senescence-associated secretory phenotype (SASP). A comparative analysis of synthetic and natural antioxidants is necessary to evaluate the efficacy of synthetic and natural antioxidants in this context.
A systematic review encompassed studies published up to July 2023, utilizing prominent databases such as PubMed, Google Scholar, Scopus, and Web of Science. To enhance the efficiency of data screening and selection, we employed Rayyan. ai, an advanced tool designed for systematic reviews.
The review encompassed 33 studies examining the impact of diverse antioxidants on cellular senescence. Findings indicated that synthetic antioxidants, such as N-acetylcysteine, and natural alternatives, like Vitamin C, demonstrated efficacy in attenuating oxidative stress and senescence markers. Notably, natural antioxidants frequently exhibited comparable or superior efficacy to their synthetic counterparts in most studies. Furthermore, the synergistic effects of antioxidant combinations sometimes yield enhanced benefits. It is worth noting that certain recently developed synthetic compounds, such as MHY2233, have shown promising results, exhibiting greater potency than established antioxidants in mitigating senescence markers.
Dietary practices and the aging process can influence these intricate processes and how they interact, serving as potential primary and secondary preventative strategies. The Mediterranean diet, dietary antioxidants, and limiting calorie intake are promising nutritional strategies. Better insight into the molecular mechanisms of aging may facilitate the development of efficient biomarkers and antioxidants for diagnosis or treatment.
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Cellular ageing or senescence, a process that induces irreversible cell cycle arrest, is a cellular response to various stresses. It is known as an important factor in tumor suppression and ageing, and age-related diseases such as osteoarthritis, glaucoma the diabetic pancreas, and neurodegenerative disorders. Thus, it is a possible therapeutic target for age-related conditions. Cellular senescence can be classified depending on its inducing factors into replicative senescence (RS), stress-induced premature senescence (SIPS), drug-induced senescence, and oncogene-induced ageing.
When cells enter the senescent stage, growth is arrested, cells undergo dramatic morphological changes, and they express senescence markers such as senescence-associated β-galactosidase (SA-β-gal), p16INK4, p53, and p21, which leads to the formation of DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). Recently, it has been demonstrated that senescent cells express the senescence-associated secretory phenotype (SASP), which is released into the environment and impacts the functions of neighboring cells. The SASP includes various transcription factors, growth factors, proinflammatory cytokines, including Interleukin (IL)-1, IL-6, and IL-8, proteases, and matrix metalloproteinases. Since many of these molecules are proinflammatory, SASP production could potentially provoke inflammation and play a significant role in numerous age-related diseases such as Alzheimer’s. Ageing cells accumulate DNA damage, which may result in irreversible growth arrest. Cell cycle checkpoints sense damage to the DNA structure and trigger complex cellular repair responses. If the DNA cannot be repaired effectively, cells go into permanent cell cycle arrest and apoptosis. A permanent cell cycle arrest occurs with cells remaining in the G0/G1 phase during senescence.
It has been reported that many signalling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), p53-p21, and p16-pRb, mainly regulate cellular ageing. Several causes are important in cell aging, including glycation, mutation, protein aggregation, telomere shortening, and oxidative stress. It has been suggested that telomere shortening is an important mechanism in cellular ageing. DNA damage is associated with the modulation of mammalian Sirtuin (SIRT), nicotinamide adenosine dinucleotide (NAD)-dependent protein deacetylase, which regulates multiple cellular processes, including senescence, metabolism, and cell cycle. SIRT modulates cellular senescence through the deacetylation of various signalling molecules, such as Nuclear Factor-κB (NF-κB), forkhead box O (FOXO), and p53.
Oxidative stress is an important cause of cellular ageing and may lead to pathological damage to cells and cell death. Oxidative stress can cause DNA damage, including DNA double-strand breaks, promote phosphorylation of γ-H2AX, activate ATM kinase activity, upregulate p53/p21 activity, and initiate cellular ageing. According to Denhan Harman’s oxidative stress theory of ageing, cells undergo ageing due to oxidative stress caused by free radicals. When the production of free radicals and reactive oxygen species (ROS) exceeds the capacity of the cells' antioxidant mechanisms, oxidative stress usually occurs. This phenomenon leads to oxidative damage to macromolecules like proteins, lipids, and DNA, contributing to cellular dysfunction and the progression of cell ageing.
Antioxidants are compounds that interact with reactive oxygen species and their derivatives to prevent them from harming the cells. They are classified according to their sources into two main groups: synthetic and natural antioxidants. Synthetic antioxidants are synthesized artificially by combinations of chemical substances. They are chemically synthesized compounds since they do not occur in nature and are added to food as preservatives to help prevent lipid oxidation. Natural antioxidants, explicitly derived from food and medicinal plants, including fruits, vegetables, spices, cereals, and traditional botanicals, may be considered bioactive compounds. Natural antioxidants in foods seem to provide metabolic benefits and are associated with a lower risk of developing several health problems. Furthermore, the protective effects of antioxidants in fruits and vegetables are related to three main groups: carotenoids, phenolic compounds, and vitamins.
The defense against oxidants declines during the ageing process, and it can be enhanced by supplementing antioxidants. Antioxidants consistently inhibit the induction of senescence phenotypes and increasing antioxidant defenses delays ageing by lowering oxidative stress. They are important to prevent cellular ageing. Antioxidant production may be an effective, preventive, and therapeutic method for the ageing process. Few systematic reviews have conducted precise comparisons between synthetic and natural antioxidants. This systematic review aims to critically compare the efficacy, mechanisms, and translational relevance of synthetic versus natural antioxidants in mitigating cellular senescence, with the goal of identifying promising candidates and therapeutic strategies for age-related interventions.
The current study is a systematic review and meta-analysis that adheres to the principles outlined in the PRISMA checklist. The study protocol has been registered within the Open Science Framework (OSF) (DOI: 10.17605/OSF.IO/B67WM).
In this systematic review, we conducted a comprehensive literature search across four significant databases: PubMed, Google Scholar, Scopus, and Web of Science (ISI). Up to July 2023, we identified 6,507 original articles. The search strategy and keywords used in each database are detailed in Table 1.
