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Novel Insights into the Roles and Mechanisms of GLP-1 Receptor Agonists against Aging-Related Diseases

Aging and aging-related diseases have emerged as increasingly severe health and social problems. Therefore, it is imperative to discover novel and effective therapeutics to delay the aging process and to manage aging-related diseases. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), one of the classes of antihyperglycemic drugs, have been recommended to manage type 2 diabetes mellitus (T2DM). Moreover, GLP-1 RAs have been shown to protect against oxidative stress, cellular senescence and chronic inflammation, which are widely accepted as the major risk factors of aging. However, their significance in aging or aging-related diseases has not been elucidated. Herein, we explain the underlying mechanisms and protective roles of GLP-1 RAs in aging from a molecular, cellular and phenotypic perspective. We provide novel insights into the broad prospect of GLP-1 RAs in preventing and treating aging-related diseases. Additionally, we highlight the gaps for further studies in clinical applications of GLP-1 RAs in aging-related diseases. This review forms a basis for further studies on the relationship between aging-related diseases and GLP-1 RAs.


Introduction
Aging due to molecular and cellular damage decreases the physical and mental capacity in a time-dependent manner. It is a significant risk factor for the higher incidences of mortality and morbidity associated with various chronic diseases [1]. The aging population is increasing worldwide and should be addressed. The number of people over 60 years is 1 billion based on the World Health Organization (WHO). Moreover, it is estimated that individuals over 60 years may possess 22% of the world's population (about 2.1 billion) by 2050 [2]. The prevalence of aging-related diseases is becoming a growing concern due to the prolonged life expectancy and rapidly aging population. Aging-related diseases, such as GLP-1 RAs are used for the clinical treatment of T2DM [4]. Table 1 summarizes the pharmacokinetic and toxicological features of GLP-1 RAs. Besides their strong hypoglycemic effects, GLP-1 RAs can significantly reduce the risk of hypoglycemia and lower lipid levels, maintain blood pressure, and enhance cardiovascular protection and renal protection [5][6][7][8][9]. Therefore, GLP-1 RAs can be used to reduce polypharmacy in older adults, especially those with multimorbidity [5,10]. A recent study showed that GLP-1 RAs might protect against chronic inflammation, oxidative stress, cellular senescence, etc., all of which are the major risk factors of aging [11][12][13][14]. Furthermore, various clinical trials have demonstrated that GLP-1 RAs play important roles in delaying and treating aging-related diseases.
This article reviews the function of GLP-1 RAs in delaying aging and ameliorating aging-related diseases, thus providing a theoretical basis and scientific guidance for clinical application of GLP-1 RAs.

Aging-related changes from different perspectives
Aging is highly complex progress associated with many biological and pathological changes. This part elucidates the underlying alterations and mechanisms in aging from different perspectives (Fig. 1).

Aging-related molecular and cellular changes
Aging is associated with complex molecular and cellular changes (Fig. 2). Several biological hallmarks representing common aging characteristics, including epigenetic alteration, genomic instability, etc., have been systematically and comprehensively elucidated [1]. Genomic instability is caused by an imbalance between DNA damage and repair. Aging-related genomic damage is caused by both extrinsic and intrinsic factors [15]. Telomeres, repetitive DNA sequences, shorten every time cells divide. DNA damage signaling pathways and cellular senescence are triggered when telomeres are very short [16]. Epigenetic alterations, such as histone acetylation, chromatin remodeling, and DNA methylation, influence gene expression and genomic integrity and promote aging [17]. Non-coding RNAs mediate epigenetic modifications that may regulate aging and aging-related diseases [18]. The balance among protein synthesis, degradation and folding is key to maintaining protein homeostasis and thus ensuring longevity. Therefore, the loss of protein homeostasis leads to aging and diseases [19][20][21]. Moreover, insulin-like growth factor 1 (IGF-1), mammalian target of rapamycin (mTOR), adenosine 5'-monophosphate activated protein kinase (AMPK), and sirtuins-mediated metabolic signaling pathways are associated with the balance between nutrient anabolism and catabolism in cells, which maintain cellular homeostasis and play essential roles in aging [1,22,23]. Mitochondria are generally considered to be sources of cytotoxic reactive oxygen species (ROS). Many studies have suggested mitochondrial dysfunction is related to aging. Nevertheless, mitochondrial ROS are not always harmful and can even extend lifespan in mammals [24]. Therefore, the roles and mechanisms of mitochondrial dysfunction in aging should be further explored. Cellular senescence is characterized by secretory phenotype (SASP), macromolecular damage, altered metabolism, and irreversible cell-cycle withdrawal. It is involved in various biological processes and aging-related diseases [25]. Cellular senescence can be regarded as the positive compensatory response to injury. However, it may become detrimental and accelerate the aging process when the regenerative capacity of tissues is depleted [1]. Stem cell exhaustion causes a decline in tissue regeneration and significantly impacts the aging process. Moreover, the aging-related physiological decline can be protected by reducing stem cell senescence in the hypothalamus [26]. Furthermore, aging is often associated with changes in cell-to-cell communication, which are features of aging-related diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD) [27]. Altogether, these biological hallmarks provide a better insight into the molecular and cellular changes in aging, building a framework for future studies.

Aging-related phenotypic changes
Molecular, phenotypic, and functional hierarchical domains establish the interlaced time and hierarchical relationship of aging. Aging is not a single cell death but a collection of phenotypes that respond to specific stimuli and follow particular dynamics. These specific aging processes are reflected in the physiological and pathological consequences of aging phenotypes. The elderly is predisposed to sarcopenia, osteoporosis, osteoarthritis, and fractures due to the progressive decline of muscle mass and strength, bone mineral density (BMD), and joint mobility. Endocrine imbalance and autonomic disorders cause dizziness, nausea, anxiety, and insomnia. Older people may also experience memory loss, mental retardation, cognitive impairment, and motor coordination deficits due to a gradual decline in the number and activity of neurons. Aging also increases arterial stiffness and decreases arterial elasticity and baroreceptor reflex sensitivity in the cardiovascular system, thus increasing blood pressure. Moreover, aging reduces the elasticity of the chest wall and lung tissue and pulmonary ventilation function in the respiratory system. Atrophy degeneration of the respiratory mucosa inhibits the removal of foreign bodies and bacterial defense, making individuals prone to respiratory infections. Aging is associated with poor digestion and absorption of nutrients, mainly due to tooth loss or loosening and atrophy of gastrointestinal mucosal. Many older adults suffer from constipation due to poor intestinal peristalsis. Renal aging is often accompanied by structural changes in the glomerulus, tubules, interstitium, and vasculature, and functional changes, including a decline in the estimated glomerular filtration rate (eGFR). These changes cause urinary disorders such as urinary frequency, urinary incontinence, or nocturia. Herein, aging-related phenotypic changes, a multifaceted decline in histological structure and organismal function, and the corresponding susceptibility to aging-related diseases have been described.

The roles of GLP-1 RAs in aging-related metabolic diseases
Aging is associated with many aging-related metabolic diseases, which cause disability and death. Compelling evidence has substantiated on the roles of GLP-1 RAs in aging-related metabolic diseases, such as T2DM, obesity, and osteoporosis.

GLP-1 RAs and T2DM
Aging impairs β-cell function and reduces insulin sensitivity and secretion, thus predisposing T2DM development in the elderly [40,41]. About 135.6 million people aged 65 to 99 years have diabetes globally, based on the latest data from the 9 th edition of the Diabetes Atlas by the International Diabetes Federation (IDF). Moreover, the number is expected to increase to 195.2 million by 2030 and 276.2 million by 2045 [42]. GLP-1 levels can also be reduced by aging in a fasting and glucosestimulated state [43]. However, GLP-1 can reverse the age-associated impairment of insulin sensitivity and glucose tolerance [44,45]. GLP-1 stimulates pancreatic cell proliferation and differentiation, thus improving pancreatic β-cell function in elderly rodents [46,47]. Exendin-4 enhances the secretion of insulin from adult human pancreatic β cells [48]. Moreover, GLP-1 therapy improves pulsatile insulin secretion in elderly diabetic patients [49]. Lixisenatide is one of the most suitable GLP-1 RAs used for T2DM pathophysiology therapy in the elderly. A pooled analysis conducted on data from six GetGoal trials suggested that lixisenatide can effectively treat elderly patients with T2DM [50]. Moreover, lixisenatide, as an add-on to oral antidiabetics (OADs), can significantly improve glycemic control in T2DM patients aged ≥65 years [51]. Another post hoc analysis showed that lixisenatide combined with basal insulin could effectively treat T2DM in patients aged ≥70 years. Notably, the effectiveness and safety of lixisenatide are virtually not affected in moderate renal insufficiency patients [52].

GLP-1 RAs and obesity
Aging is associated with gains in fat mass and the loss of muscle mass, which leads to obesity among older individuals [57]. Several factors regulate these agingrelated changes in body compositions, including physical inactivity, resting metabolic rate reductions, hormone levels decline, and blunted lipolysis [57][58][59][60]. However, the precise mechanisms underlying the changes in body composition associated with aging are unknown. GLP-1 RAs regulate body fat accumulation and weight loss via three direct or indirect ways. First, GLP-1 RAs can regulate satiety and suppress appetite through the central nervous system. Intracerebroventricular GLP-1 treatment strongly inhibits food intake in fasted rats [61]. A recent crossover, randomized, placebo-controlled trial showed that liraglutide could affect the neural reaction to food cues in middle-aged T2DM patients [62]. Notably, GLP-1 receptors were firstly proved to exist in human brains [62]. Second, GLP-1 RAs influence gastrointestinal function by inhibiting gastric motility and delaying gastric emptying [63][64][65]. Third, GLP-1 RAs directly act on adipose tissue, promote brown remodeling of white adipose tissue and fat mobilization, accelerating fat burning and thus achieving sustained weight loss [66].
Liraglutide was approved by the U.S. Food and Drug Administration (FDA) (2014) for the treatment of obesity and chronic weight management in obese adolescents aged 12-17 [67,68]. Studies have also assessed the safety and effectiveness of semaglutide in obese patients with or without T2DM for an enhanced therapeutic approach in the future [69]. However, there are few studies related to a weight loss of GLP-1 RAs focusing on older adults. A STEP 2 study showed that semaglutide significantly decreases the weight of T2DM patients with overweight or obesity (55.3±10.6 years) [6]. A clinical trial with 68 older adults with obesity and prediabetes found that liraglutide can significantly enhance weight loss. Moreover, liraglutide-mediated weight loss substantially improves insulin resistance, glucose tolerance, SBP, and triglyceride concentration. However, 79% of patients treated with liraglutide experienced gastrointestinal side effects [70]. Another prospective study with nine subjects demonstrated that a 24-week liraglutide treatment could effectively reduce fat mass in overweight and obese elderly with T2DM [71]. Overall, liraglutide can effectively promote and maintain weight loss in the elderly. However, further studies should assess the effect of semaglutide, a novel weight-loss therapeutic drug.

GLP-1 RAs and osteoporosis
Aging reduces bone strength, thus increasing the risk of fracture (osteoporosis) in the elderly. The imbalance between bone resorption and bone formation during bone remodeling causes osteoporosis. GLP-1 treatment can improve the viability levels of MG-63 and TE-85 osteoblastic cell lines, suggesting that GLP-1 may bind to specific GLP-1 receptors on osteoblasts, thereby promoting bone formation [72]. GLP-1 influences bone metabolism, possibly through ATP-induced c-Fos activation [73]. Moreover, the expression of GLP-1 receptors is increased during the osteogenic differentiation of adipose-derived stem cells (ADSCs) [74]. GLP-1 stimulates the osteoblast differentiation and inhibits adipocyte differentiation in human ADSCs via ERK and Wnt/GSK-3β/β-catenin pathways [75,76]. GLP-1 promotes the proliferation of human mesenchymal stem cells (hMSCs), reducing apoptosis and preventing their differentiation into adipocytes. Further evidence has shown that MEK and PKC pathways mediate the impacts of GLP-1 on these cells [77]. In addition, GLP-1 RAs may inhibit bone resorption by stimulating calcitonin release from thyroid C-cells [78].
A clinical study showed that exenatide treatment for 44 weeks does not affect BMD and serum markers of bone metabolism [79]. Another two-centered clinical trial reported no effect on BMD or bone turnover markers after 24 weeks of exenatide treatment in newly diagnosed T2DM patients [80]. Furthermore, GLP-1 RAs are not correlated to the increase in bone fracture risk [81]. Similarly, a meta-analysis showed that GLP-1 RAs are not related to fracture risk [82]. The level of serum GLP-1 decrease in older patients with fractures. However, vitamin D is positively correlated with GLP-1, suggesting GLP-1 has a bone-protective effect [83].

The roles of GLP-1 RAs in aging-related neurodegenerative diseases
Neurodegenerative diseases are caused by the loss of neurons or myelin sheaths, which deteriorate over time, resulting in dysfunction. GLP-1RAs play an essential role in aging-related neurodegenerative diseases.

GLP-1 RAs and AD
AD is characterized by the deficits in cognition, memory, and learning. Emerging evidence shows that GLP-1 RAs are associated with AD. Impaired brain insulin signaling in T2DM is closely related to AD pathogenesis [84]. Exendin-4 can protect against apoptosis and regulate GLP-1/insulin/IGF-1 pathway in middle-aged T2DM rat brains [85]. Liraglutide can significantly increase hippocampal CA1 pyramidal neuron numbers and improve memory function in SAMP8 mice [86]. Liraglutide can also cross the blood-brain barrier (BBB) of 7-month-old APP/PS1 mice, reducing amyloid plaque, decreasing the inflammation response, and increasing young neurons [87]. Similar results have also been obtained in older APP/PS1 mice after three years [88]. The above two studies demonstrate that liraglutide has protective effects in the early and late AD stages. Beside reducing the levels of amyloid-beta (Aβ) protein precursor and Aβ in 3xTg-AD mice brains, exendin-4 can ameliorate Aβ toxicity and oxidative damage at the cellular level [89]. Moreover, exenatide can also significantly reverse transcriptomic alterations underlying brain endothelial cells (ECs) aging at a molecular level [90].
Liraglutide treatment can significantly increase blood-brain glucose metastasis and prevent a decrease in cerebral metabolic rate for glucose (CMRglc) in AD patients compared with placebo [91]. An exploratory analysis suggested that long-term treatment with dulaglutide has beneficial effects on cognitive impairment in patients aged ≥50 years with established or newly diagnosed T2DM [92]. Moreover, a 6-month liraglutide treatment increases CMRglc in AD patients but does not affect Aβ levels and cognitive scores [93]. An 18-month phase II clinical trial showed that exenatide treatment reduces Aβ42 levels in plasma neuronal extracellular vesicles (EVs). However, no significance in cortical thickness and volume, cognitive measures, or biomarkers were found between the exenatide group or placebo [94].
Meanwhile, it is unknown whether liraglutide has neuroprotective benefits in middle-aged persons with AD [95]. A multi-center study with 206 patients randomized to liraglutide is currently underway [96], and better results are highly expected in future research.

GLP-1 RAs and PD
PD is shared among the elderly. Liraglutide and lixisenatide can cross the BBB, thus enhancing neurogenesis [97]. NLY01, a brain-penetrant GLP-1 RA, exerts neuroprotective effects by blocking the microglialmediated transition of astrocytes into A1 neurotoxic phenotypes in PD mice [98]. Furthermore, GLP-1 has neurotrophic effects of protecting against human neuronal apoptosis at the cellular level [99]. Altogether, these results point to the function of GLP-1 RAs in treating PD.
Clinical evidence suggest that a 12 month-exenatide treatment can significantly improve motor and cognitive functions in PD patients [100]. Moreover, the motor and cognitive advantages could persist for an extended period after exenatide withdrawal [101]. Exenatide also improves practically defined off-medication motor scores in patients with moderate PD. However, it is unknown whether exenatide treatments can alter the course of the underlying PD [102]. A systematic review also suggested the function of exenatide in the improvement of motor impairment for PD patients requires deep research [103]. Hence, exenatide may represent a new therapeutic drug for treating PD, but additional studies are needed to evaluate its long-term effecacy in treating everyday symptoms.

The roles of GLP-1 RAs in aging-related cardiovascular diseases
Aging represents a crucial risk factor in the occurrence, development and outcome of cardiovascular diseases. GLP-1 RAs can benefit aging-related cardiovascular diseases, such as vascular aging, atherosclerosis, and hypertension.

GLP-1 RAs and vascular aging
Experimental and clinical studies have shown that GLP-1 RAs decrease the risk of adverse cardiovascular events. However, the detailed mechanisms involved are unknown. Vascular aging contributes to the pathology of cardiovascular diseases. GLP-1/exendin-4 can attenuate ROS-induced ECs senescence via an AMP/PKAdependent pathway [11]. Exendin-4 can also significantly alleviate angiotensin (ANG) II-induced superoxide generation and the subsequent vascular smooth muscle cells (VSMCs) senescence by targeting Rac1 and Nrf2 [104,105]. Exenatide can ameliorate vascular aging stimulated by a high-fat diet in ApoE-/-mice by modulating inflammation and oxidative stress response [106]. Moreover, exenatide can protect endothelial dysfunction caused by ischemia-reperfusion injury in humans by opening K ATP channels [107]. Moreover, the dipeptidyl peptidase 4 (DPP-4)/GLP-1 axis can prevent vascular aging and maintain ischemia-induced neovascularization in mice [11,108]. In ApoE-/-mice, increased DPP-4 levels promote diet-associated vascular aging in the presence of chronic stress [109]. Moreover, inhibiting DPP-4 would ameliorate chronic stress-related vascular aging, potentially through the improvements of oxidative stress and vascular inflammation [110]. DPP-4, mediated by the GLP-1/GLP-1R axis, can also regulate chronic stress-associated inflammatory cell production and bone marrow hematopoietic stem cell activation [111]. Overall, these findings imply a regulatory mechanism of GLP-1 RAs in vascular aging and indirectly suggest roles of GLP-1 RAs in managing cardiovascular diseases.

GLP-1 RAs and atherosclerosis
Atherosclerosis is common in the elderly. Aging alters the vascular structure and function, such as intimal thickening, inflammation, and lipid deposition, thus accelerating the progression of atherosclerotic diseases [112]. However, liraglutide can inhibit the formation of atherosclerotic plaques and enhance the stability of early atherosclerotic plaques by binding to the GLP-1 receptor [113]. Liraglutide can also ameliorate atherogenesis by reducing serum-advanced glycation end products (AGEs) expression of receptor for advanced glycation end products (RAGE) [114]. DPP-4 inhibition decreases chronic stress-related carotid artery thrombosis, possibly by improving oxidative stress [115]. DPP4 inhibition can also attenuate oxidative stress, plaque inflammation, and proteolysis related with GLP-1-mediated adiponectin production [109]. Monocytes and macrophages, primary immune cells, are involved in the inflammatory processes in the atherosclerotic lesion. GLP-1 RAs induce antiatherosclerotic effects by reducing monocyte/macrophage accumulation in the arterial vessel, regulating proinflammatory mediators, and modulating immune cell phenotypes [116][117][118][119]. Moreover, liraglutide enhances bone marrow-derived macrophages in mice and MΦ2 phenotypes in human THP-1 [117]. Liraglutide can also inhibit VSMCs proliferation through AMPK signaling activation and cell cycle regulation, thereby delaying atherosclerosis [120].
A prospective study showed that an 8-month liragluide treatment could reduce triglycerides (TG), lowdensity lipoprotein-cholesterol (LDL-C), and total cholesterol (TC), but increase high-density lipoprotein cholesterol (HDL-C) in T2DM patients [7]. The treatment can also significantly decrease carotid intima-media thickness (CIMT), a surrogate marker of subclinical atherosclerosis [7,121]. Liraglutide can significantly reduce LDL-C, TG, and CIMT levels in T2DM and metabolic syndrome [122]. Altogether, these studies indicate that GLP-1 RAs are strongly associated with hyperlipidemia and atherosclerosis, especially in middleaged and older patients.

GLP-1 RAs and hypertension
Hypertension is ubiquitous in the elderly, and more than half of people aged 45-75 years in China and the United States suffer from hypertension [123]. Liraglutide combined with OADs, such as rosiglitazone, glimepiride, and metformin have antihypertensive effects [124]. Several recent studies have investigated whether GLP-1 RAs alone can exert blood-pressure-lowering effects. Liraglutide can decrease SBP by 1.2 mmHg [8]. In SUSTAIN-6 trial, respectively, the mean SBP in the semaglutide group receiving 0.5 mg and 1.0 mg was 1.3 mm Hg and 2.6 mm Hg lower than the placebo [125]. Similarly, compared with placebo group, the SBP was 2.6 mmHg lower in the oral semaglutide group in the PIONEER 6 trial [126]. Moreover, considerable evidence supports that GLP-1 RAs are also associated with a modest reduction in diastolic blood pressure (DBP) in middle-aged and older patients with T2DM [127,128].
The principal mechanisms of antihypertensive effect of GLP-1 RAs may consist of the following four fronts. First, GLP-1 RAs promote vasodilation. Chai et al. found that GLP-1 enhances muscle microvascular blood volume (MBV) in overnight-fasted adult male rats by increasing the production of nitric oxide (NO) [129]. Kim et al. also indicated that liraglutide induces atrial natriuretic peptide (ANP) secretion, thereby promoting vasorelaxation [130]. Notably, GLP-1 can directly affect relaxing rat conduit arteries, independently of NO and the endothelium [131]. GLP-1 infusion can regulate vasorelaxation in the brachial artery of middle-aged patients with T2DM and coronary artery disease [132]. Second, GLP-1 RAs facilitate and promote natriuresis. GLP-1 receptor can be expressed on atrial cardiomyocytes. GLP-1 RAs can increase cAMP via activating GLP-1 receptor and mediate ANP release, leading to urine sodium excretion and blood pressure (BP) reduction [130]. GLP-1 RAs may also increase urinary sodium excretion by regulating Na + /H + exchanger in renal tubules [133,134]. Third, GLP-1 RAs indirectly control BP through weight loss. Weight loss is correlated with BP reduction in middle-aged and older T2DM patients [135]. Fourth, GLP-1 RAs are involved in the central control of BP. Liraglutide attenuates the progression of hypertension in spontaneously hypertensive rats by activating brainstem dopamine beta-hydroxylase (DBH) neurons and suppressing sympathetic nerve activity [136].

The roles of GLP-1 RAs in aging-related kidney diseases
Aging alters the kidney structure, such as decreased renal mass and cortical thickness, glomerulosclerosis, glomerular basement membrane (GBM) thickening, interstitial fibrosis, and tubular atrophy [137]. The eGFR declines by about 5%-10% per decade after 30 years [138], one of the most predominant functional changes of renal aging. It is usually difficult to distinguish common kidney diseases in the elderly, such as diabetic kidney disease (DKD), acute kidney injury (AKI), and chronic kidney disease (CKD), which are caused by normal aging or are secondary to the disease development. However, aging is undoubtedly a vital part of the pathogenesis of these kidney diseases in the elderly [137,139,140]. GLP-1 RAs have been used by almost all clinical trials for kidney outcomes in the diabetic population, the majority of whom are elderly. Herein, we differatiate between patients with DKD and those with diabetes and CKD.
Chronic kidney disease mainly affects elderly populations worldwide, and it is a growing concern [150]. AWARD-7 trial investigated the glycemic control and kidney outcomes of dulaglutide in patients with T2DM and moderate-to-severe CKD. Dulaglutide was associated with less eGFR decline than insulin glargine at 52 weeks of follow-up [151]. The post-hoc analysis of SUSTAIN 1-7 trials showed that semaglutide decreases UACR [152]. Cardiovascular trails have shown that GLP-1 RAs can benefit CKD patients [153,154]. A meta-analysis evaluated seven cardiovascular studies of GLP-1 RAs, stating that GLP-1 RAs treatment can reduce broad composite kidney outcomes, including the sustained decline in eGFR, emergence of new macroalbuminuria, progression to end-stage kidney disease (ESKD), or death from renal causes [154]. GLP-1 RAs reduce the risk of serious renal events compared with other hypoglycemic drugs, such as sulfonylureas and DPP-4 inhibitors [155,156]. However, GLP-1 is less effective in preventing the progression of kidney diseases than SGLT-2 inhibitors in some cases [157]. The KDIGO (Kidney Disease: Improving Global Outcomes) 2020 clinical practice guidelines recommend that patient preferences, comorbidities, eGFR, and cost should be considered when approaches of choosing hypoglycemic drugs other than SGLT-2 inhibitors and metformin, if needed GLP-1 RAs are preferred, especially for the T2DM and CKD patients with an eGFR <30 ml/min per 1.73 m 2 or those treated with dialysis [158]. The findings illustrate that GLP-1 RAs can improve DKD and CKD management.
In people over 60 years, the incidence of communityacquired AKI has increased by more than 3-fold [159]. Risk factors for AKI in this population include agingrelated hemodynamic alterations, kidney aging, comorbidities and medications [140]. A few cases of GLP-1 RAs-induced AKI have been reported in middleaged and elderly patients [160][161][162]. However, it has been reported that GLP-1 RAs are not correlated to the enhanced risk for AKI. It was found that the AKI rate was similar in liraglutide and placebo groups in LEADER trial [9]. Additionally, exenatide did not raise the incidence of acute renal failure (ARF) [163]. It has also been documented that SGLT2 inhibitors exert a lower risk for AKI than GLP-1 RAs [164]. However, the roles of GLP-1 RAs in AKI development among the elderly have not been fully established.

5 The roles of GLP-1 RAs in musculoskeletal degenerative diseases
Musculoskeletal degenerative diseases, such as osteoporosis, osteoarthritis and sarcopenia are considerable health challenges among the elderly. The protective roles of GLP-1 RAs on osteoporosis have been elaborated in some detail.
GLP-1 receptor levels decreased significantly in rat models of knee osteoarthritis, while liraglutide inhibited the expression of inflammation-related proteins through the PKA/CREB signaling pathway [165]. Liraglutide attenuated cartilage degeneration in rat models [166]. At the cellular level, the GLP-1 receptor mediates the protective effects of liraglutide in chondrocytes, preventing endoplasmic reticulum stress and apoptosis [166]. In addition, liraglutide exerted beneficial effects on human chondrocytes by inhibiting oxidative stress, mitigating inflammatory responses and suppressing extracellular matrix degradation [167]. These results suggest the clinical potential of GLP-1 RAs in treating osteoarthritis.
Sarcopenia is associated with an aging-related progressive decline of muscle mass, quality, strength and function. In C2C12 myoblasts, liraglutide induced myogenesis through GLP-1 receptor and downstream cAMP-dependent pathways [168]. Additionally, the disrupted structure of myofibrillar was restored by liraglutide in some muscle atrophy models [168]. Analogously, exendin-4 and dulaglutide increases muscle mass and function through the suppression of myostatin and muscle atrophic factors and enhancement of myogenic factors [169]. Moreover, a clinical study showed liraglutide treatment was associated with improved skeletal muscle index (SMI) [71]. Nevertheless, current research on the relationship between GLP-1 RAs and sarcopenia are limited.

Prospective therapeutic applications
The elderly are susceptible to various diseases, while GLP-1 RAs have multiple pleiotropic effects. GLP-1 RAs have the potential to be used or can be used in the treatment of various aging-related diseases, including T2DM, overweight or obesity, hypertension, hyperlipidemia, atherosclerosis, vascular aging, kidney disease, AD, PD, osteoporosis, osteoarthritis and sarcopenia. In addition, hepatocyte senescence-associated hepatic fat accumulation and steatosis should be evaluated [170]. This is because GLP-1 RAs have shown various benefits in managing non-alcoholic fatty liver disease (NAFLD), alleviating hepatic inflammation, metabolic dysfunction, insulin resistance and lipotoxicity [171][172][173]. With the continued decline in physical functioning, loss of capacity and socioeconomic status, the elderly are more likely to experience isolation, loneliness, and consequent psychological problems. In this respect, GLP-1 RAs can improve cognitive functions in patients with mood disorders [174]. Therefore, GLP-1 RAs are potential adjunctive antidepressants. However, although GLP-1 RAs are safe and well-tolerated in most cases, given the higher rates of gastrointestinal adverse effects in GLP-1 RAs treated patients, their clinical administrations in elderly patients should be carefully and comprehensively considered. The therapeutic results, pharmacokinetic characteristics, administration dosage, frequency, and duration vary for different types of GLP-1 RAs. It is essential to determine the specific roles of each drug and their combined actions with other agents. Clinical trials should be performed to investigate the roles of GLP-1 RAs in elderly patients with multimorbidities, thus maximizing their efficacies while minimizing their side effects.

Perspectives and conclusions
GLP-1 RAs can safely and effectively lower blood sugar levels and reduce weight as a new hypoglycemic or weight loss drug. We have reviewed the diverse mechanisms underlying the protective function of GLP-1 RAs against aging-related diseases, especially in middleaged and aged adults. Several hallmarks of aging have all been elucidated systematically and comprehensively. We strive to study the molecular, phenotypic, and functional hierarchical domains, establishing the interlaced time and hierarchical relationship of aging. Plenty of clinical evidence mainly focusing on middle-aged and aged adults support the established or potential benefits of GLP-1 RAs on a variety of common aging-related diseases, including metabolic diseases, neurodegenerative diseases, cardiovascular diseases, kidney diseases, and musculoskeletal degenerative diseases. Nevertheless, the complex mechanisms underlying the relationship between GLP-1 RAs and aging-related diseases have not yet been fully identified. Although GLP-1 RAs have great potential for a wide range of human diseases, there are many hurdles to bring them to the clinic. Large-scale studies are needed to verify the safety and efficacies of GLP-1 RAs in decreasing polypharmacy in elderly patients with multimorbidities.