The role of non-coding RNAs (ncRNAs), which include miRNAs, in gene regulation is substantial across all eukaryotic organisms. Research on these little but powerful regulators has increased in recent years, illuminating their extensive effects on many different biological processes, as well as their extraordinary adaptability and complex regulatory networks (Cui et al., 2019; Abd El Fattah et al., 2022; El-Sheikh et al., 2022; Li et al., 2022; Bakr et al., 2023).

DNA sequences that are referred to as miRNA genes or clusters of genes that are either exclusively or cooperatively generated as miRNA molecules are the molecular antecedents of miRNAs. On the other hand, miRNAs can be discovered in the areas of non-translated or intron genes that are responsible for the production of proteins. Hereafter, we have outlined the canonical and non-canonical processes of biogenesis (Rodriguez et al., 2004; Olena and Patton, 2010).

Within the canonical biogenesis process, the encoding of miRNA gene sequences by RNA polymerase II culminates in the primary miRNA (pri-miRNA) phase, which is the first step in the canonical pathway. The complex is responsible for transforming the pri-miRNA into the pre-miRNA, which is the precursor miRNA. The process of miRNA modification by Dicer begins with its transport to the cytoplasm via Exportin 5 (Denli et al., 2004; Newman and Hammond, 2010; Wei et al., 2021; Erturk et al., 2022). Single-stranded miRNAs that have reached maturity are responsible for directing the functional effector complex to modify complementary RNA targets (Figure 1) (Shang et al., 2023). The processing of some miRNAs will be carried out in a manner that is not deemed to be canonical. This particular area of study has been established with the support of a variety of various methods, such as transfer RNAs (tRNAs) derived miRNAs and miRtrons, in addition to small nucleolar RNAs (snoRNAs)-derived miRNAs and the independent approach that DICER has taken. The creation of these protocols allowed for the standardization of the many processes that are involved in the generation of miRNA (Ruby et al., 2007b; Babiarz et al., 2008; Ergin and Çetinkaya, 2022).

Transfer RNAs are an alternative source of non-canonical miRNAs. Angiogenin (ANG) or DICER uses the unique architecture of tRNAs as a substrate, cleaving the tRNA stem into fragments of tRNA-derived RNA (tDR) (Hasler et al., 2016). Also, some evidence suggests that AGO proteins can control gene expression in a manner analogous to miRNAs by loading certain tRNA segments (Abdelfattah et al., 2014). miRtrons are a kind of non-canonical pri-miRNAs that are encoded within the introns of coding genes. Like normal introns, miRtrons undergo early processing by nuclear splicing machinery, where they stabilize into hairpins with a shorter stem than conventional pri-miRNAs (Westholm and Lai, 2011). The debranching enzyme 1 (DBR1) is responsible for lariat-debranching rather than DROSHA/DGCR8 for these shorter hairpin configurations (Ruby et al., 2007a).

There is growing evidence indicating that some snoRNAs serve as a source for non-canonical miRNAs (Patterson et al., 2017). Notably, the processing of snoRNA-derived miRNAs and the stability of snoRNAs are influenced by key elements of the canonical miRNA biogenesis pathway, including DICER and DGCR8 (Langenberger et al., 2013). DGCR8, in conjunction with other proteins, could break down snoRNAs during their processing, therefore impacting the processing of miRNAs produced from snoRNAs (Macias et al., 2015). To mature, miRNAs may need the AGO2 slicer activity in a DICER-independent mode, which occurs when the stem-loop structure is too short to be cleaved by DICER (Cheloufi et al., 2010). Some of the benefits of small hairpin RNAs (shRNAs) processing that is not dependent on DICER include the ability to target genes in tumor cells that lack DICER and the preferential loading of small interfering RNAs (siRNAs) into AGO2, which improves RNAi (Herrera-Carrillo and Berkhout, 2017).

Even though miRNAs have been known for a considerable amount of time, it is only recently that their major role in an organism’s functioning has been understood. Cancer, skin issues, a broad range of lung disorders, neurological diseases, and other age-related diseases have all been the subject of extensive miRNA studies (Ugalde et al., 2011; Condrat et al., 2020; Semina et al., 2021). Evidence suggests that miRNAs can have a positive impact on a wide variety of critical biological processes. Inflammation, cell differentiation, and angiogenesis are all examples of such processes. Several complicated disorders have been linked to the improper regulation of non-coding RNAs. It is possible to affect cell function if the processing of these small but powerful regulators is disrupted (Abd El Fattah et al., 2023; El-Sheikh et al., 2023; Salman et al., 2023).

Research into complicated illnesses such as cancer, cardiovascular disease, and diabetes mellitus is facilitated by an increase in the quantity of data relevant to the interactions between miRNA and aging. These interactions apply to the process of aging. MiRNAs have also been shown to be responsible for the modulation of pathways that are involved in the sensing of nutrition (Ismail et al., 2019; Sohel, 2020; Abdelmaksoud et al., 2023).

To regulate a wide range of biological processes, miRNAs play an essential role. These regulatory molecules are likely to play a part in the etiology of inflammation and aging, and they might be utilized as therapeutic targets. There is little doubt about their involvement. Their actions are very context-dependent since miRNAs are engaged in post-transcriptional control of many messenger RNAs. Several factors impact these processes. These include the degree to which miRNAs interact with genes, the amount and affinity of miRNAs with their targets, the type of cell, the level of miRNA expression, and the concentration of miRNAs inside cells (Smith-Vikos and Slack, 2012; Quintanilha et al., 2017b; O'Brien et al., 2018). Epigenetics examines genetic control and acquired traits. Many epigenetic changes occur, including DNA methylation, histone modification, and miRNA channel silencing. (Al-Noshokaty et al., 2022; Rizk et al., 2022). The complicated mechanism that governs gene expression relies on miRNAs by the utilization of miRNA sponges, miRNA-Masking Antisense Oligonucleotides, or antisense oligonucleotides that specifically target miRNAs (AMOs) (Lima et al., 2018). In miRNA-sponge technology, mRNA molecules containing several target miRNA binding sites are expressed to act as a “sponge” or decoy for the target miRNAs (Ebert and Sharp, 2010). In other cases, instead of inhibiting the target miRNA, miR-Mask molecules shield the mRNA whose function is desired to retain. This technique is also known as BlockmiR, target protectors, or target site blockers (Wang, 2011; Beavers et al., 2015).

One major risk factor for chronic illnesses in the elderly is aging. By attaching base pairs to their target mRNAs, miRNAs control the silencing of genes that occur post-transcription. Upon analyzing whole blood from healthy adults, recent studies found nonlinear variations in age-related miRNAs, with age having a greater influence than sex. In healthy aging, a transition in miRNAs to their 5′mature form was proved. With distinct disease biomarker sets for young and elderly patients, the inclusion of ill individuals highlighted pan-disease and disease-specific modifications in aging profiles (Meder et al., 2014; Fehlmann et al., 2020).

The altered expression of aging miRNA across various human and animal tissues has been confirmed through multiple studies (Smith-Vikos and Slack, 2012). Alterations in the expression of proteins, mRNA, and miRNA associated with aging and growth in the prefrontal cortex of rhesus macaques and humans have been noticed throughout their lives (Somel et al., 2010). Similar modifications in miRNA levels have been described in human skeletal muscle with aging (Drummond et al., 2011), as well as in bodily fluids like serum (Zhang H. et al., 2015). This lays the groundwork for recognizing the connection between disease and healthy aging as well as the creation of disease biomarkers particular to a person’s age (Table 1).

Extracellular vesicles (EV) are considered fragments of dead or senescent cells secreted upon physiological or pathological processes (Misawa et al., 2020). EVs are used to send signals for exchanging information among cells via a complex packet of lipids, and proteins rich in ncRNAs and miRNAs. They are also known as exosomes or microvesicles and have an important role in aging (Tkach and Théry, 2016; Cooks et al., 2018).

Our current knowledge of the significant role miRNAs perform in age-related disorders is not sufficiently comprehensive due to the varied nature of intracellular and extracellular miRNAs. Nonetheless, interesting research has been done that will help us grasp the fundamental causes of these diseases. Herein, we will discuss a growing number of publications about particular miRNAs and their involvement in different age-related disorders.

With the first FDA-approved small RNA drugs entering clinical medicine, continuous research for the microRNA (miRNA) class of small RNAs has expanded its preclinical and clinical research application. The growing evidence from the huge number of reports indicates that miRNAs could be put to significant utility as biomarkers for pathogenic conditions, modulators of drug resistance, and/or drugs for medical intervention in almost all human health conditions (Hanna et al., 2019). In a study involving 16 non-Hispanic men aged between 50 and 60, whose lifespans ranged from 58 to 92 years, PCR arrays were used to track changes in miRNA levels in their serum over time. Notably, variations in the expression of these miRNAs were observed. Specifically, at the age of 50, 24 miRNAs were found to be significantly more active, while 73 showed reduced activity in those who lived longer (76–92 years), compared to those who had shorter lifespans (58–75 years). For the group that lived longer, miR-373-5p showed the highest increase in activity, whereas miR-15b-5p was the most decreased. Over the years, a strong correlation between the lifespan and the activity levels of nine specific miRNAs was observed, with significant changes noted in six of these (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, 1225-3p) when comparing the longer-lived to the shorter-lived participants. These six miRNAs affect 24 proteins linked to aging, such as PARP1, insulin-like growth factor-1 receptor (IGF1R), and IGF2R. Based on the findings, activity patterns of these six miRNAs are suggested to be valuable indicators of aging (Smith-Vikos et al., 2016). This suggests that a single miRNA candidate could have the ability to control whole biological pathways related to aging, thereby promoting longevity.

Despite significant advancements in preclinical studies, miRNA-based therapies are still in the preliminary phase of development. A limited number have advanced to clinical trials, with none making it to phase III or receiving approval from the FDA. Additionally, some have been discontinued due to concerns about toxicity. These obstacles underscore the need to overcome current obstacles to fully realize the potential of miRNA-based treatments in clinical settings (Seyhan, 2024). Currently, no miRNAs are undergoing clinical trials for longevity enhancement. However, the promise of miRNAs as treatments for a range of diseases is evident, and further research is crucial to assess their practicality in clinical environments.

Macromolecules such as carbohydrates, fatty acids, and amino acids can protect or induce aging through miRNA modulation. Beta cell dysfunction is associated with overexpressed miR-29a in beta cells of Langerhans supplemented by high glucose media (Bagge et al., 2012). Moreover, miR-29a is also induced by saturated fatty acids repressing insulin receptor signaling −1 (IRS-1) and increasing insulin resistance in myocytes (Yang et al., 2014c) (Table 2). A high-fat diet is shown to increase the expression of miR-21 which promotes liver carcinogenesis (Heng et al., 2016). In addition, a high-fat diet could overexpress miR-195 impairing insulin sensitivity and glycogen metabolism in the liver (Yang et al., 2014d). Moreover, a high-fat diet is involved in the pathogenesis of atherosclerosis through upregulation of miR-210 inducing endothelial cell apoptosis (Li et al., 2017).

Hyperglycemia also induces the expression of miR-21 reducing the tumor suppressor protein phosphatase and tensin homolog deleted in chromosome 10 (PTEN) mediating the pathogenesis of nephropathy in diabetic patients (Dey et al., 2011). While protein is important for kidney health, low maternal protein intake accelerates epithelial-mesenchymal transition in the later adult life of the offspring through increasing expression of miR-192 and miR-200 (Sene et al., 2018). Xylobiose intake as an alternative to sucrose and present in bamboo can be favorable for diabetic patients as it regulates hepatic lipogenesis by overexpressing miR-122a/33a resulting in reducing triglyceride levels and inflammatory cytokines (Lim et al., 2016).

Non-optimum levels of micronutrients such as selenium, zinc, and vitamin D generate several aging-related diseases (McCann and Ames, 2011; Prasad, 2012; Sinha et al., 2013). They are included in miRNA modulation being included in their structure. Selenium is one of the micronutrients that has gained attention recently, due to its incorporation into selenoproteins such as glutathione peroxidase or other antioxidant enzymes (Bellinger et al., 2009). An in vitro experiment utilizing colorectal cancer cell lines in a selenium-deficient environment results in a changed expression of miR-185 with a feedback mechanism regulating selenoproteins as glutathione peroxidase 2 (Maciel-Dominguez et al., 2013). In selenium-deficient rats, miR-374 is overexpressed leading to a dysregulated Wnt signaling pathway and cardiac dysfunction (Xing et al., 2015). Moreover, combining resveratrol with selenium nanoparticles enhanced the effectiveness of resveratrol against Alzheimer’s disease reducing neuroinflammation through downregulating miR-134 (Abozaid et al., 2022). Vitamin D deficiency in diet upregulates miR-148a and miR-122-5p and it is related to bone loss and eventually osteoporosis in post-menopausal women (Al-Rawaf et al., 2021). Moreover, zinc deficiency is linked to an increased risk of esophageal cancer due to overexpression of miR-223, miR-21, and miR-31 (Fong et al., 2016).

Vitamin B12 and folic acid are essential for several biological processes and are also important for maternal nutrition for the offspring’s health. Imbalanced nutritional levels in maternity are linked to insulin resistance and type 2 diabetes mellitus in the offspring’s adult life through upregulating miR-483 which limits fats in the adipose tissue (Figure 3) (Mahajan et al., 2019).

Phenolic compounds or flavonoids act as anti-aging agents by regulating miRNA function. Olive oil rich in phenols intake in middle age increased the miRNA expression of miR-484, miR-137-3p, miR-27, and miR-124-3p resulting in reduced brain plasticity and improving neurological and behavioral function (Luceri et al., 2017a). Another study investigated the impact of grape seed intake rich in procyanidin on diabetic rats, it was found that the flavonoids of grape seed modulate glucose metabolism and improve pancreatic function through downregulating the expression of miR-1249, miR-483, miR-30c-1, and upregulating miR-3544 expression (Figure 3) (Castell-Auví et al., 2013).

Chronic pistachio intake, rich in unsaturated fat, minerals, and vitamins, modulates insulin resistance through downregulating miR-192 and miR-375 involved in increasing plasma glucose levels and insulin resistance (Hernández-Alonso et al., 2017) (Table 2). Probiotics modulate different inflammatory diseases. For instance, probiotics such as Lactobacillus rhamnosus and Lactobacillus delbrueckii downregulate the expression of miR-181a and miR-155 involved in the inflammatory response of systemic lupus erythematosus (Vahidi et al., 2018). In addition, the intake of probiotics such as bifidobacterium modulates cell cycle senescence by regulating miR-34 and increasing Sirtuins 1 resulting in wellbeing and reduced aging (Haslberger et al., 2021). Nicotinamide mononucleotide supplementation enhances the antiaging properties of the aging aorta by upregulating miR-146a, and miR-203 and downregulating miR-99b and miR-127 (Figure 3) (Kiss et al., 2019).

MiRNAs are increasingly acknowledged as key players in aging and longevity. Several miRNAs directly impact lifespan by affecting major aging pathways. While most insights into miRNAs that influence longevity come from invertebrate studies, the mechanisms, and roles of miRNAs in aging are similarly observed in mammals.

Mechanisms in which miRNAs control gene expression often involve their “seed” sequences interacting mostly with the 3′-end, and less frequently with the 5′-end, of mRNA that is transcribed from targeted genes. In the past decade, many studies have focused on both quantitative and qualitative evaluations of miRNA expression, revealing significant alterations in miRNA expression patterns in different diseases. Consequently, analyzing miRNA expression profiles can be a crucial method for diagnosing and treating diseases (Gulyaeva and Kushlinskiy, 2016).

Cellular and molecular damage gradually accumulates over time, triggering the intricate process of aging. Ultimately, this accumulation results in a generalized decline in physiological functions, an elevated risk of mortality, and the end of life. Even while a variety of environmental and random circumstances have a role in an individual’s aging process, there is a significant basic inherited component to aging too. It has been proposed that systems crucial for organism development and cell proliferation may indirectly affect gene expression patterns that govern aging and senescence (Campisi, 2005). Furthermore, it has been found that several elements that play a universal function in all species control how long Caenorhabditis elegans survives. These include heat-shock factors (HSFs), sirtuins, AMP-activated protein kinases (AMPKs), mitogen-activated protein kinases (MAPKs), and signaling through the insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway (Smith-Vikos and Slack, 2012).

Aging research is progressively concentrating on alterations in nutrient sensing pathways, recognizing their potential to be modulated through pharmacological interventions as well as dietary modifications (Longo et al., 2015). Important nutrition sensing mechanisms, including the AMPK/Sirtuin/PGC1 and IGF1/PI3K/AKT/mTOR pathways, can be disrupted by aging. Numerous cellular activities, including protein synthesis, cell cycle progression, DNA replication, autophagy, stress response, and glucose homeostasis, are dependent on these pathways. Environmental factors such as pollution, physical exercise, smoking, and food can alter the biological mechanisms linked to aging.

Caloric restriction (CR) is recognized as an effective dietary strategy to extend lifespan healthily, highlighting diet as a key environmental factor influencing the aging process (Longo et al., 2015; Most et al., 2017). Dietary choices and compounds can impact molecular aging pathways, thereby altering the quality and healthfulness of aging. Recent research indicates that miRNAs play a role in regulating age-related activities, such as DNA replication, cellular aging (senescence), and programmed cell death (apoptosis). Additionally, miRNAs have been found to influence nutrient sensing pathways Thus, miRNAs not only regulate nutrient sensing pathways but can also be influenced by dietary factors (Figure 4) (Micó et al., 2017).

Aging and age-related diseases occur due to multi-faceted pathologic incidences. One of these pathologic incidences is the chronological increase in senescent cells (SCs) which undergo irreversible cell cycle arrest, and simultaneously increase the release of various chemicals that stimulate inflammation and oxidative stress signaling pathways. This SCs phenotype is identified as a senescence-associated secretory phenotype (SASP) (Prasnikar et al., 2021). Therefore, foods high in polyphenols and other bioactive compounds, which have anti-inflammatory and antioxidant properties, may be used as “anti-senescence” or “senolytic” foods in a nutraceutical strategy for enhanced cellular longevity and better aging (Gurau et al., 2018). Indeed, nutraceuticals rich in polyphenols have shown excellent results in many age-related diseases owing to their antioxidant and anti-inflammatory effects (Zhor et al., 2023).

Epigenetic dysregulation is a part of the aging process, and many nutraceuticals are regarded as promising candidates to counteract these age-related epigenetic changes (Bacalini et al., 2014). Likewise, changes in miRNA expression play a prominent role in regulating the mRNA expression of genes involved in the shaping of aging and age-related diseases (Matai and Slack, 2023a). Therefore, it’s expected that diets or nutraceuticals that control specific miRNA expression can enhance healthy aging or halt the progression of age-related diseases. So far, it has been reported that dietary intake of micronutrients, macronutrients, vitamins, minerals, flavonoids, and polyphenols can modulate the expression of various miRNAs (Dimmeler and Nicotera, 2013; Milenkovic et al., 2013; Beckett et al., 2014; Yu et al., 2021). However, future research will need to determine whether dietary manipulation of miRNAs contributes to the prevention or treatment of age-related illnesses.

As we age, we experience a low-grade systemic inflammation, a condition that has been previously termed “inflammaging.” This condition is marked by an increase in the levels of pro-inflammatory cytokines (mostly TNF-α and IL-6) and circulating acute-phase proteins (Franceschi et al., 2000; Franceschi, 2007). Frailty and the onset and advancement of age-related illnesses, such as cancer, osteoporosis, neurodegenerative diseases, atherosclerotic cardiovascular diseases, and type 2 diabetes mellitus are linked to this inflammaging phenomenon (Vasto et al., 2007; Cevenini et al., 2013). Numerous research provided evidence in favor of the theory that achieving extreme longevity likely necessitates a unique control of inflamma-miRs gene expression (ElSharawy et al., 2012; Olivieri et al., 2013). Quercetin, a plant flavonol, shielded CCD-18Co myofibroblasts from reactive oxygen species (ROS) and prevented inflammation by enhancing the activity of antioxidant enzymes and stimulating the upregulation of miR-146a, a negative regulator of pro-inflammatory nuclear factor kappa B (NFκB) activation (Noratto et al., 2011b).

Changes in miRNA expression were evident in brain aging and neurodegenerative diseases. Whether these changes in miRNA expression are the cause or consequence of brain aging is still a riddle (Somel et al., 2010). In the study of Luceri et al. (Luceri et al., 2017b), mice fed extra-virgin olive oil (EVOO) rich in phenols (H-EVOO) for 6 months demonstrated improvements in their motor and cognitive functions when compared to controls given the same olive oil but devoid of phenolics (L-EVOO). Interestingly, mice fed L-EVOO demonstrated a substantial modification in the expression of 175 miRNA, unlike mice fed H-EVOO which showed alterations in the expression of only 20 miRNAs compared to young mice. These results demonstrate the capacity of phenolic-rich olive oil to mitigate age-related modifications in miRNA expression. Moreover, miR-29, miR-30, miR-34, miR-101, miR-124, and miR-181, which have been linked to neurodegenerative diseases or senescence (Dimmeler and Nicotera, 2013), were among the miRNAs that were either low or not expressed in the cortex of young and H-EVOO-fed mice and strongly expressed in mice fed L-EVOO (Figure 5).

As stated by Sir William Osler in his historical textbook in 1898: “Longevity is a vascular question, which has been well expressed in the axiom that man is only as old as his arteries” (COOK, 1908). Indeed, aging is intricately linked to the development of CVDs. Growing older is the primary risk factor for vascular endothelial dysfunction, which raises the possibility of CVDs, one of the leading causes of death in developed nations (Gaidai et al., 2023). These CVDs are mostly attributable to the sedentary lifestyle in the developed world, characterized by a diet rich in saturated fats and sugars (Kirkpatrick and Maki, 2021). On the contrary, a reduction in the onset of CVDs could be attributable to health-promoting dietary patterns, such as the Mediterranean diet rich in nutraceuticals (Accardi et al., 2016). An in vitro study conducted by Noratto et al. (2011a) showed that treatment of lipopolysaccharide-induced inflammation in human umbilical vein endothelial Cells (HUVEC) with a polyphenol extracted from grapes reduced the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1) as a result of modulating the expression of miR-126.

Bone health deteriorates and the incidence of osteoporosis increases with increased age (Pignolo et al., 2021). Vitamin D is a key regulator of bone health by promoting calcium absorption, and its active form, 1,25-dihydroxyvitamin D (1,25-(OH)₂-D), acts as a steroid hormone and exerts pleiotropic effects (Veldurthy et al., 2016). In a previous study by Jiao et al., 2020, the beneficial role of miR-140-5p in bone health was disclosed. Results revealed that miR-140-5p promoted osteogenic differentiation and led to a significant increase in osteocalcin expression, bone mineral density, and bone mass in addition to enhancing bone healing of miR-140-5p-transgenic mice with fracture. In the study conducted by Luo et al., 2018, a positive correlation between miR-140-5p and 1,25-(OH)₂-D was revealed. In this study, miR-140-5p was upregulated in 2 types of murine osteoblasts treated with 1,25-(OH)₂-D. The enhanced expression of miR-140-5p by 1,25-(OH)₂D3 occurred through transcriptional activation of the vitamin D receptor and this activated vitamin D/vitamin D receptor/miR-140-5p axis led to a downstream inhibition of MAPK signaling in osteoblasts (Figure 5).

Cancer is regarded as one of the age-related diseases due to the build-up of mutations throughout life (Laconi et al., 2020). miR-100 and miR-125b were shown to have tumor suppressor effects and their expression levels were found to be reduced in several cancers. The study conducted by Giangreco et al., 2013 revealed another health benefit for 1,25-dihydroxy vitamin D3 in prostate cancer patients, in which vitamin D3 supplementation managed to enhance the expression of these tumor-suppressive miRNAs. This suggests that miRNAs may be important physiological mediators of vitamin D3 action in the early detection and prevention of prostate cancer.

All-trans-retinoic acid treatment upregulates miR-29a and miR-142-3p. In patients with acute myeloid leukemia (AML) and healthy controls, enhanced expression of either miRNA-induced myeloid differentiation. This shows that miR-29a and miR-142-3p are important regulators of healthy myeloid differentiation and that the development of AML is influenced by their decreased expression (Wang et al., 2012). Selenite is a nutraceutical and dietary form of selenium. It was shown that treatment of human prostate cancer cells (LNCaP) with selenite upregulated the expression of p53 and miR-34b/c, where miR-34 is known to target the p53 gene, and induction of p53 enhances apoptosis. This indicates that selenite may be beneficial for both the prevention and treatment of human prostate cancer (Sarveswaran et al., 2010).

Resveratrol, found in red grapes, is a popular bioactive compound that was extensively studied during the last 2 decades and found to have a myriad of protective effects against a wide variety of diseases (Meng et al., 2020). Adding to its well-known benefits, resveratrol can be protective against age-related problems such as hearing loss in which miR-34a was found to be involved in resveratrol’s protective mechanism. In the study of Xiong et al., 2015, miR-34a expression, p53 acetylation, and apoptosis were found to be enhanced in the cochlea of C57BL/6 mice with aging, however, an age-linked reduction in SIRT1 was noted. In the inner ear HEI-OC1 cell line, an inverse relation was revealed between miR-34a and SIRT1 expression; where the overexpression of miR-34a inhibited SIRT1 expression, which led to a rise in p53 acetylation and apoptosis. Inversely, silencing of miR-34a led to a significant increase in SIRT1 expression, and consequent reduction in p53 acetylation, and apoptosis. Resveratrol, being a SIRT1 activator, following 2-month administration, significantly attenuated miR-34a expression, which led to a significant reduction in hearing loss and hair cell loss in C57BL/6 mice (Figure 5).

Epigallocatechin-3-O-gallate (EGCG) is the most abundant and active polyphenol in green tea. The study of Rasheed et al., 2016 investigated the effect of EGCG in an in vitro model of osteoarthritis, one of the age-related chronic diseases. The study revealed that EGCG inhibited COX2 expression and prostaglandin E2 (PGE2) production via upregulating miR-199a-3p expression in an IL-1β-stimulated human osteoarthritis chondrocytes.

Notably, the majority of the data supporting the modification of miRNA by nutraceuticals in aging comes from cell lines and some of this data comes from in vivo pre-clinical studies. Translational research that can advance these studies from bench-to bedside or from pre-clinical to clinical studies in older adults will help determine if nutraceutical manipulation of miRNAs can improve healthy aging or halt the occurrence or progression of age-related diseases.

miRNAs have a crucial function in regulating gene expression post-transcription. They have emerged as important regulators of cellular functions and can be altered by dietary factors. Specific miRNAs selectively target genes responsible for encoding proteins and enzymes involved in pathways that sense nutrition. This targeting has the potential to greatly impact the regulation of the aging process (Lai et al., 2019). Several studies have demonstrated that diet and nutraceuticals can potentially control the expression of miRNAs linked to aging, neurodegenerative disorders, and brain tumors. Nutrients possess the capacity to control the amounts of miRNA, which plays a pivotal role in influencing gene expression. Therefore, the control of miRNA aging through nutrition and nutraceuticals holds great potential for treating age-related diseases and improving overall healthy aging.

The approaches for employing miRNA-based interventions in age-related diseases encompass the identification of disease-linked miRNAs, the manipulation of miRNA expression through nutrition and nutraceuticals, the creation of miRNA-based therapeutics, and the investigation of miRNAs as biomarkers for age-related diseases. These methods show potential for creating new strategies to encourage healthy aging and tackle age-related ailments (Lai et al., 2019).

Studies have demonstrated that different miRNAs play a role in the regulation of age-related illnesses, including AD, age-related macular degeneration, neurological disorders, and cancer (Natoli and Fernando, 2018; Eshkoor et al., 2022). Studies have shown that nutritional components and nutraceuticals can control the activity of miRNAs that have a role in age-related disorders. This suggests that they could be used as potential treatments (Ghosh et al., 2021).

miRNAs have been recognized as promising candidates for therapeutic intervention in age-related macular degeneration and other age-related ailments. Several miRNA-based medicines are currently undergoing Phase 2 clinical studies, indicating the efficacy of miRNAs as therapeutic targets (Natoli and Fernando, 2018).

This topic investigates the impact of nutrition on the alteration of gene expression through epigenetic mechanisms associated with miRNAs. This study assesses the impact of nutrients and bioactive chemicals on the expression of miRNA, which may have consequences for regulating inflammation and chronic diseases (Quintanilha et al., 2017a). Specific miRNAs have been proposed as prospective biomarkers, diagnostic tools, or desirable targets for the management and treatment of age-related illnesses, such as age-related macular degeneration (Cruz-Aguilar et al., 2023).