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Let-7 as a Target in Aging-Related Diseases: History
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Contributor: Lin Xu

Lethal-7 (let-7) was discovered in Caenorhabditis elegans (C. elegans) and plays an important role in development by regulating cell fate regulators. Accumulating evidence has shown that let-7 is elevated in aging tissues and participates in multiple pathways that regulate the aging process, including affecting tissue stem cell function, body metabolism, and various aging-related diseases (ARDs). Moreover, recent studies have found that let-7 plays an important role in the senescence of B cells, suggesting that let-7 may also participate in the aging process by regulating immune function. Therefore, these studies show the diversity and complexity of let-7 expression and regulatory functions during aging.

  • Let-7
  • Aging
  • aging-related diseases

1 . Introduction

Aging is a complex systemic physiological process characterized by progressive deterioration of tissue and organ functions and reduced repair capacity, leading to increased susceptibility to aging-related diseases (ARDs) and increased risk of death. The aging process is associated with various physiological and pathological molecular mechanisms, many of which are differentially expressed by age-dependent transcriptional regulation, resulting in changes in multiple cells, tissues and organs, and even lifespan [1][2]. In addition, aging is a driver of a variety of age-related diseases, including neurodegenerative diseases, age-related cataracts, osteoporosis, etc. [3][4][5]. Although many interventions have been used clinically to slow the progression of aging-related diseases, their effectiveness is still limited [6][7]. Therefore, a better understanding of the molecular mechanisms of the aging process and identification of aging biomarkers and possible therapeutic targets for ARDs is performed to pave the way for future research on aging biology and new antiaging therapies.

Let-7 was originally identified as a heterochronic gene in Caenorhabditis elegans (C. elegans) and also named lethal-7 (let-7) because its deletion is lethal during development [8]. In mammals, let-7 has been successively found to regulate cell differentiation, development, and apoptosis and to be involved in glucose metabolism  [8][9][10][11]. It also acts as a tumor suppressor to regulate cell proliferation, and its dysregulation and expression are associated with disease progression [12][13]. Recent studies have revealed that let-7 not only increases in aging tissues and acts as an important regulator of cell and tissue senescence in aging organisms [14] but also plays a key role in the development of aging-related diseases represented by Alzheimer’s disease [15][16]. These studies further suggest that let-7 is a potential intervention target molecule in the pathological process of aging.

2. Let-7—The Role in Tissue Aging and ARDs

2.1. Let-7 and the Nervous System

Let-7 is widely expressed in the aging central nervous system, resulting in decreased neuron formation and the self-renewal of neural stem cells. Hmga2, highly expressed in fetal and young animal neural stem cells (NSCs), promotes self-renewal of neural stem cells at least in part through downregulation of p16 Ink4a and p19 Arf [17]. Studies have shown that Hgma2 mRNA contains seven let-7 binding sites, for example, let-7b binding to Hmga2 3′UTR negatively regulates its expression [18]. Thus, due to increased let-7 levels in NSCs of aged animals, reduced Hmga2 expression leads to elevated cell cycle inhibitors [19], thereby halting NSC renewal [16]. In addition, in older neurons, let-7 upregulation inhibits the expression of Lin-41, an important promoter of anterior ventral microtubule (AVM) axon regeneration [20], which in turn inhibits AVM axon regeneration and ultimately leads to a decline in neuronal regeneration capacity. Additionally, the binding of let-7 and Lin-28 controls the maintenance of DA9 synaptic polarity [21], which is important in aging and neurodegenerative diseases.
Alzheimer’s disease (AD) is a devastating neurodegenerative disease caused by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain[16], and multiple miRNAs are involved in this critical pathological process [22]. The major component of these plaques, β-amyloid peptide (Aβ), is derived from the amyloid precursor protein (APP) through the sequential action of β- and γ-secretase [16]. Drosophila melanogaster and C. elegans do not have the APP gene, but both express the amyloid precursor protein gene APL-1 [23], which is controlled by let-7 and its targets. For instance, let-7 transcriptionally regulates APL-1 through Hbl1, Lin-41, and Lin-42 and is critical for the development of AD [24]. Moreover, it is also known that let-7 is negatively regulated by miR-107. Interestingly, studies have shown that miR-107 downregulated beta amyloid cleaving enzyme (BACE1), which generated amyloid beta peptide (Aβ) fragments by cleaving APP, leading to amyloid beta deposition promoting the development of AD [25]. However, whether the apparent down-regulation of miR-107 in AD [26] negatively up-regulates let-7 expression [27] and promotes the development of AD needs to be further verified. In addition, dysregulation of miRNAs leads to dysfunction of intracellular and extracellular biochemical processes and ultimately to neuronal cell death, which is another factor influencing AD [28][29]. For example, the expression of let-7a, let-7b and let-7e are found to be upregulated in high cholesterol diet–induced AD progression in a late-onset rabbit mode [30], suggesting that let-7 may be involved in the pathological process of cholesterol metabolism associated with AD. Another study reported that the cerebrospinal fluid of AD individuals was specifically enriched in let-7b or let-7e [31] and interacted with TLR7 receptors as signaling molecules, further activating IRAK-4 through phosphorylation, and the activated IRAK-4 stimulates caspase-3 to activate the TLR7 signaling pathway, which eventually leads to neuronal degeneration [32]. Recent studies suggest that abnormal autophagy may be a major risk factor for AD [33], as shown by Gu et al., who revealed that let-7a overexpression in concert with the PI3K/AKT/mTOR signaling pathway enhances Aβ1-40-induced neurotoxicity through the regulation of autophagy [34].

2.2. Let-7 and the Vision System

Let-7 is involved in the regulation of retinal development and the cell cycle, and its expression gradually increases with age [35]. For example, let-7b and let-7c increase significantly during normal vitreous aging, and both of them are expressed by Muller glia cells and detected in their extracellular vesicles [35]. Further studies have found that let-7c targets hyaluronic acid synthase 2 (Has2), a major component of vitreous synthase, which affects vitreous development and remodels during aging by regulating hyaluronic acid content with binding to the 3′UTR sequence, promoting the structural changes of the extracellular matrix [35]. Studies have shown that let-7 is associated with several age-related retinal diseases. For example, dysregulation of let-7 family members has been detected in the vitreous fluid of both age-related macular degeneration and proliferative retinopathy patients [15][36]. However, the specific role of let-7 in aging-related eye diseases remains to be elucidated.

2.3. Let-7 and the Reproductive System

The trade-off between the allocation of resources and energy for reproduction and growth versus somatic maintenance has been central to the “evolutionary optimization” theory of aging [37], and the removal of germline stem cells by germline laser ablation or GLP-1/NOTCH mutants can indeed extend the lifespan of nematodes [38]. A study found that knocking out Lin28 extends lifespan and promotes germline stem cells into meiosis in nematodes, resulting in far fewer germline stem cells in young adults [39]. Importantly, as the best-known downstream effector of Lin28, let-7 stimulates DAF-16 translocation by targeting AKT-1/2, which is essential for Lin28-induced longevity and smaller germline progenitor cell pools, and the reproductive stem cell and lifespan effects of Lin28 RNAi are eliminated in let-7, AKT-1/2, and DAF-16 mutant worms, indicating that the Lin28/let-7/AKT/DAF-16 axis plays an important role in balancing reproduction and somatic cell maintenance [40]. Furthermore, Lin28 is specifically expressed in the niche of testicular stem cells, directly binding and protecting Upd mRNA (a stem cell self-renewal factor), maintaining the number and function of central cells in the testicular stem cell ecotone [41]. However, Lin28 expression decreases with age, causing let-7 to bind IGF-II messenger RNA by targeting protein (Imp) to reduce Upd expression, leading to a consequent loss of germline stem cells [42]. Furthermore, a downregulation of let-7c is detected in patients with premature ovarian failure (POF) compared to normal women [43], implying an active role of let-7c in healthy follicle development. However, the function of let-7g in follicles seems to be different from other family members because it is highly expressed during atresia [44], directly targets the anti-apoptotic gene MAP3K1, and causes the expression and dephosphorylation of the transcription factor FoxO1, which in turn induces GC (granulosa cell) apoptosis [45]. Meanwhile, let-7g targets TGFBR1 to block the TGFβ signaling pathway and increase caspase-3 activity and the apoptosis rate [46]. Fortunately, in a typical mouse model of premature ovarian failure (POF) induced by a high-fat, high-sugar (HFHS) diet, thymopentin promotes the transcriptional activation of Lin28A by stimulating the expression of transcription factor YY2, inhibiting the activity of let-7 family miRNAs and alleviating the senescence of ovarian granulosa cells, ultimately achieving the therapeutic effect on POF in mice [47].

2.4. Let-7 and the Immune System

Aging is accompanied by adaptive immune system senescence including the dysfunction of B and T lymphocytes [48], and miRNAs have a key regulatory role in immune cell development and function [49][50]. There is growing evidence to support the role of let-7 in the regulation of the immune system, including let-7 as a key player in the regulation of B-cell antibody production, T-cell activation, and macrophage responses, etc. [51][52][53][54]. However, little is known about the relationship between let-7 and the immune system during aging. A reduction in the size of the pre-B-cell pool in aging mice has been reported [55], accompanied by intrinsic B-cell defects [56], but the underlying causes of these changes remain to be elucidated. Koohy et al. found that compared with young cells, the level of IRS1 protein in aging pro-B cells and pre-B cells decreased, while the expression level of let-7 increased [57]. Importantly, downregulation of Irs1 and upregulation of let-7 expression are major components of the transcriptional downregulation of the insulin-like growth factor signaling pathway in aging, and therefore upregulation of let-7 in the aging B-cell precursors targeting Irs1 and other components at the post-transcriptional level is likely to result in reduced responsiveness to insulin/IGF signaling [57]. Interestingly, there are striking alterations in the chromatin at a novel potential precursor RNA for the let-7b and -7c2 in pre-B cell senescence [57], which is indicative of an interplay between epigenetic and post-transcriptional mechanisms in shaping gene expression. This finding suggests that aging affects the regulation of key signaling pathways at multiple levels.

2.5. Let-7 and Other Organizations

Muscle loss is a main contributor to aging-related diseases, and strategies to improve muscle regeneration during aging are urgently needed. The role of individual miRNA in skeletal muscle formation has been extensively studied, and many miRNAs have been shown to be involved in this process [58]. As reported in the research, let-7b and let-7e are significantly elevated in skeletal muscle in the elderly and cause skeletal muscle loss by targeting cell cycle regulators CDK6, CDC25A, and CDC34 [59]. Other studies have shown that single inhibition of let-7 promotes muscle cell differentiation increased muscle mass in mice [11][60][61]. Surprisingly, inhibition of a combination of five miRNAs containing let-7 increased activation of focal adhesion kinase (FAK), AKT, and p38 mitogen-activated protein kinase (MAPK) during myogenic differentiation and improved myotube formation and insulin-dependent glycogen synthesis [62]. In addition, let-7-targeting paired cassette 7 (PAX7) and IL-6 in senescent muscle and oculopharyngeal muscular dystrophy (OPMD), a disease that shares molecular characteristics with senescent muscle, leads to reduced muscle regeneration and functional degeneration [63].
Osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (MSC) maintain homeostasis in vivo under physiological conditions. With the increase of age, the balance between adipogenesis and osteogenic differentiation of MSCs may be disrupted, resulting in excessive accumulation of bone marrow adipocytes and reduction of bone mass, which is related to age-related bone metabolic diseases (such as osteoporosis) [64]. Let-7 is found to positively regulate osteogenic differentiation and negatively regulate lipogenic differentiation of HADSCs by inhibiting Hmga2 while negatively regulating lipogenic differentiation, suggesting that let-7 is therefore a positive regulator of skeletal development [65]. Importantly, let-7c and let-7d expression in mouse femurs increased after birth and peaked at 4 weeks, followed by a rapid decline after bone maturation, indicating that let-7 expression coincides with the timing of skeletal development. Thus, downregulation of let-7 expression in bone with increasing age reduces osteogenesis by inhibiting osteogenic differentiation of HADSC. Notably, another study found that let-7g expression is downregulated in osteoporosis, but let-7g mimics inhibit ALP activity and mineral deposition in osteoblasts, which in turn controls osteoblast differentiation [66].

Collectively, let-7 is highly expressed in multiple tissues, including brain, retina, and muscle, which regulates the differentiation function of multi-tissue stem cells by targeting different genes (Figure 1) to regulate aging-related pathways, thereby affecting the development of aging and related diseases, suggesting that let-7 plays critical role in the process of aging and ARDs and is a promising target for intervention.

Figure 1. Target genes regulated by let-7 in aging and aging-related diseases in multiple tissue systems.

This entry is adapted from the peer-reviewed paper 10.3390/biom12081070

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