Probiotics and prebiotics in the treatment of functional constipation in the elderly individuals

Abstract

Functional constipation (FC) in elderly individuals is a significant health issue that adversely affects their quality of life, with recent studies indicating a close relationship between this condition and gut microbiota dysbiosis. This review aims to explore the role of the gut microbiota in FC in elderly individuals, analyze the mechanisms of the gut-brain axis, and evaluate the potential use of microecological agents, including probiotics and prebiotics, in modulating the gut microbiota and alleviating constipation symptoms. By integrating the latest research findings, this study seeks to provide new perspectives and intervention strategies for the management of FC in elderly individuals.

Key Words: Functional constipation; Elderly; Gut microbiota; Microbiota dysbiosis; Gut-brain axis; Probiotics; Prebiotic

Core Tip: Probiotics and prebiotics may play a significant role in managing functional constipation (FC) in elderly individuals by modulating gut microbiota and alleviating symptoms. The interplay between gut microbiota dysbiosis and the gut-brain axis further complicates FC, necessitating a multifaceted treatment approach that includes microecological agents to enhance gut health and improve the quality of life for older adults. Recent studies have highlighted the potential use of probiotics and prebiotics in managing FC, particularly in the elderly individuals.

INTRODUCTION

Functional constipation (FC) in elderly individuals is a prevalent condition that is characterized by infrequent bowel movements, difficulty in passing stools, or a sensation of incomplete evacuation. The quality of life of older adults is strongly affected by this ailment, which can cause discomfort, anxiety, and other possible problems, including fecal impaction. According to epidemiological data, approximately 30% of the senior population experiences FC; additionally, demographic variables, including age, sex, and coexisting medical problems, can differentially affect this condition[1]. This illness has multiple causes, including altered gut motility, decreased physical activity, and dietary habits. Moreover, the aging process itself leads to physiological changes in the gastrointestinal (GI) tract, including decreased colonic motility and altered gut microbiota composition, which may worsen symptoms of constipation[2]. An understanding of the complexities of FC in elderly individuals is important for establishing effective treatment strategies for this disorder. A major factor in preserving the digestive system (which is important for several physiological processes, such as metabolism, digestion, and immune system function) is the gut microbiota. For the fermentation of dietary fibers, which results in short-chain fatty acids (SCFAs) that enhance colonic health and improve bowel regularity, a balanced gut microbiome is necessary[3]. Numerous GI problems, including FC, are related to dysbiosis, which is defined as an imbalance in the gut microbiota. Research has shown that changes in the composition of the microflora may increase gut motility and intestinal permeability, which further exacerbates the pathophysiology of constipation[1]. There is considerable crosstalk between the host and the gut microbiota, and new research has shown that the use of the gut microbiome represents a therapeutic approach for managing FC in elderly individuals[4]. The concept of the gut-brain axis (GBA) explains the reciprocal communication that occurs between the GI system and the central nervous system (CNS). This relationship is mediated by many pathways, including neural, endocrine, and immunological processes[5]. In FC patients, dysregulation of this axis may lead to altered gut motility and sensitivity, thereby further complicating the disease[6]; moreover, the GBA is very important in elderly individuals, wherein cognitive deterioration and emotional variables may affect GI function. An understanding of the role of the GBA in FC may provide insights into new therapeutic approaches that address both the physiological and psychological aspects of this disorder.

Microecological agents, including probiotics, prebiotics, and synbiotics, have attracted increasing attention for their potential ability to improve gut health and alleviate symptoms of FC in elderly individuals. Live microbes that provide health advantages, such as probiotics, can aid in the restoration of microbiological balance and the improvement of gut motility[7]. Conversely, prebiotics are foods that are not digestible and that aid in the growth of beneficial gut microbes, which improves the general health and function of the gut[8]. Moreover, synbiotics, which are mixtures of prebiotics and probiotics, have shown promise in improving the effectiveness of FC treatment and modulating the composition of the gut microbiota[9]. According to clinical research, these microecological agents may result in notable increases in the frequency and consistency of the bowel, thus emphasizing that they may be used as therapeutic options for elderly individuals[10]. In summary, the care of individuals with FC must involve a comprehensive strategy that considers the interactions that occur between the gut microbiota, the GBA, and the use of microecological agents. To clarify the different ways in which these therapies may improve the quality of life of older individuals who are experiencing this prevalent GI issue and improve their gut health, more research is necessary.

PATHOPHYSIOLOGICAL MECHANISMS OF FC IN ELDERLY INDIVIDUALS

FC is a prevalent issue occurring among the elderly population and is characterized by infrequent bowel movements and difficulty in passing stools. The Rome IV criteria define FC based on specific symptoms, including fewer than three bowel movements per week, straining during defecation, and a sensation of incomplete evacuation[11]. This classification is vital for understanding the complexity of constipation, particularly in older adults, who often experience multiple comorbidities that can exacerbate their GI issues. The pathophysiology of FC is multifactorial and involves neuromuscular dysfunction of the colon, altered gut motility, and changes in the gut microbiota. Aging can lead to a decrease in the number of interstitial cells of Cajal, which are essential for coordinating gut motility; moreover, alterations in the enteric nervous system (ENS) may further complicate bowel function[12]. Additionally, psychological factors, dietary habits, and medication side effects play significant roles in the development of constipation.

Definition and classification of FC according to the Rome IV criteria

The Rome IV criteria provide a standardized framework for diagnosing functional GI disorders, including FC. According to these criteria, FC is diagnosed when patients exhibit two or more of the following symptoms over the previous three months before diagnosis: (1) Straining during at least 25% of bowel movements; (2) Lumpy or hard stools in at least 25% of bowel movements; (3) A sensation of incomplete evacuation in at least 25% of bowel movements; and (4) Fewer than three bowel movements per week[13]. This classification emphasizes the subjective experiences of the patient, which is crucial for an accurate diagnosis and treatment planning. The criteria also distinguish between primary and secondary constipation, with primary constipation being idiopathic and secondary constipation resulting from underlying medical conditions or medication effects. An understanding of these classifications can aid health care providers in developing targeted treatment strategies for elderly patients suffering from constipation, thereby ensuring a comprehensive approach to management.

Common causes of constipation in elderly individuals

Constipation in elderly individuals is often multifactorial, with several common causes having been identified in clinical studies. Age-related physiological changes, such as decreased GI motility and altered colonic function, can significantly contribute to the prevalence of constipation in this population[14]. Additionally, chronic medical conditions, such as diabetes and Parkinson's disease, can exacerbate constipation because of their effects on autonomic nervous system function and gut motility[15]. Polypharmacy is another critical factor, as many elderly patients take medications that can induce constipation, including opioids, anticholinergics, and certain antihypertensives[16]. Lifestyle factors, such as reduced physical activity and inadequate dietary fiber intake, further compound this issue. Moreover, psychological factors, including depression and anxiety, can also lead to changes in bowel habits, thus making it essential for health care providers to consider a holistic approach to treatment that addresses both the physiological and psychosocial aspects of constipation in elderly individuals.

Intestinal motility and defecation mechanisms

The mechanisms of intestinal motility and defecation are complex and involve a coordinated interplay between the ENS, smooth muscle contractions, and rectal sensation. In healthy individuals, the process of defecation begins with distension of the rectum, which activates sensory pathways that signal the need to defecate[17]. However, in elderly patients, this sensory feedback can be impaired due to conditions such as rectal hyposensitivity, thereby leading to difficulties in recognizing the urge to defecate[18]. Additionally, age-related changes in the ENS and a decrease in the number of interstitial cells of Cajal can disrupt normal colonic motility, thus resulting in slower transit times and increased stool hardness[19]. Furthermore, the coordination of voluntary and involuntary muscle contractions during defecation can be affected by pelvic floor dysfunction, which is more common in older adults. Therefore, an understanding of these mechanisms is crucial for developing effective treatment strategies for constipation in elderly individuals, as interventions may need to target both the physiological and functional aspects of bowel movements.

RELATIONSHIPS BETWEEN THE GUT MICROBIOTA AND FC

FC is a prevalent GI disorder that can significantly impact an individual's quality of life. Recent studies have increasingly focused on the role of the gut microbiota in the pathogenesis of this condition. The gut microbiota, which is a complex community of microorganisms residing in the GI tract, plays crucial roles in various physiological processes, including digestion, metabolism, and immune function. Dysbiosis (or an imbalance in the composition of the gut microbiota) has been associated with various GI disorders, including FC. Research has indicated that individuals with FC often exhibit a reduced diversity of gut microbiota, which is characterized by a decrease in beneficial bacteria such as Bifidobacteria and an increase in potentially harmful bacteria such as Bacteroidetes[20]. These alterations can disrupt normal gut motility and lead to constipation symptoms. Furthermore, the gut microbiota produces SCFAs and other metabolites that influence gut motility and intestinal health, thus suggesting that a healthy microbiota composition is essential for preventing and managing FC[20].

Composition and function of the gut microbiota

The composition of the gut microbiota is highly individualized and influenced by various factors, including diet, age, and lifestyle. In healthy individuals, a diverse gut microbiota is typically characterized by a balanced ratio of Firmicutes to Bacteroidetes, along with a significant presence of beneficial bacteria such as Lactobacillus and Bifidobacterium. These bacteria contribute to gut health by fermenting dietary fibers into SCFAs, which serve as energy sources for colonocytes and play a role in maintaining the intestinal barrier[21]. In contrast, individuals with FC often display reduced microbial diversity and an altered composition, which can lead to impaired fermentation processes and decreased SCFA production. This dysbiosis can result in decreased intestinal motility and increased gut transit time, thereby exacerbating constipation symptoms[22]. Additionally, the gut microbiota interacts with the host immune system, thus influencing inflammatory responses and gut motility via various signaling pathways. Therefore, an understanding of the composition and function of the gut microbiota is crucial for developing targeted interventions for FC.

The impact of dysbiosis on FC

Dysbiosis has been increasingly recognized as being a contributing factor to the development and persistence of FC. Research has shown that individuals with this condition often demonstrate a significantly different gut microbiota profile compared to healthy controls, which is characterized by a reduction in beneficial bacterial species and an increase in pathogenic species[6]. This imbalance can disrupt normal gut function, thereby leading to decreased production of SCFAs, which are vital for maintaining gut motility and overall GI health. Moreover, dysbiosis can impair the GBA, thus affecting communication between the gut and the CNS, which plays a crucial role in regulating bowel movements[6]. Interventions aimed at restoring a healthy gut microbiota, such as the use of probiotics, prebiotics, and dietary modifications, have demonstrated promise in alleviating symptoms of FC. For example, studies have demonstrated that probiotics can increase gut microbiota diversity, improve SCFA production, and ultimately promote improved bowel regularity[23]. Therefore, strategies targeting dysbiosis may offer a novel therapeutic approach for the management of FC.

Changes in the gut microbiota characteristics of elderly patients with FC

Elderly individuals often experience FC due to a combination of physiological changes, dietary factors, and comorbid conditions. Research has indicated that the composition of the gut microbiota in older adults significantly differs from that in younger individuals, whereby older adults often exhibit reduced diversity and altered microbial profiles[24]. In particular, studies have shown that elderly patients with FC tend to have lower levels of beneficial bacteria, such as Lactobacillus and Bifidobacterium, as well as higher levels of potentially harmful bacteria, which may contribute to the development of constipation[25]. These changes in the gut microbiota can lead to decreased SCFA production and impaired gut motility, thus exacerbating constipation symptoms in this population. Furthermore, the presence of frailty in elderly individuals with constipation has been associated with even more pronounced dysbiosis, which highlights the need for targeted interventions that consider both the gut health and overall physical condition of elderly individuals[26]. An increased focus on gut microbiota imbalances via dietary modifications, probiotics, and other therapeutic strategies may be particularly beneficial for improving bowel function and quality of life in elderly patients with FC.

THE ROLE OF THE GBA IN FC

The GBA is a complex network of communication that connects the CNS to the GI tract, which correspondingly plays a key role in homeostasis (this bidirectional signaling pathway allows the brain to influence gut function and vice versa). Additionally, the GBA in FC is a common functional GI disorder that is very important because it emphasizes the interaction of psychological factors, the gut microbiota and GI motility, which correspondingly causes changes in the GBA, thus causing altered gut motility and sensory processing and ultimately leading to the symptomatology of FC. Psychological stressors can worsen GI symptoms, and the role of the GBA in FC is also highlighted by the fact that mental stressors can aggravate GI symptoms, thus emphasizing the value of treating both gut health and mental health[27].

Basic concepts of the GBA

The GBA is a complex network that integrates neural, hormonal, and immunological signaling between the gut and the brain. It encompasses the ENS, which is often referred to as the "second brain” due to its substantial autonomy and ability to regulate GI functions independently of the CNS. The GBA operates through various pathways, including the vagus nerve, which transmits signals between the gut and the brain, as well as through the release of neuroactive substances such as neurotransmitters and hormones. The gut microbiota also plays a crucial role in this axis by producing metabolites that can influence brain function and behavior. Dysregulation of the GBA can lead to various GI disorders, including FC, as it affects gut motility, secretion, and sensation. Thus, an understanding of the fundamental mechanisms of the GBA is essential for developing effective interventions for FC and related disorders[28,29].

Interaction of the nervous, endocrine, and immune systems

The interactions among the nervous, endocrine, and immune systems are integral to the functioning of the GBA. There are many different ways in which these systems communicate with each other; for example, the gut microbiota has the ability to affect how many neurotransmitters (such as serotonin) are produced, which is essential for controlling mood and gut motility. Stress may also cause activation of the hypothalamic-pituitary-adrenal axis, which releases cortisol, thus potentially impairing gut function and causing constipation symptoms. The immune system also mediates inflammation in the gut, which has the potential to alter sensation and motility. Due to this complicated interaction, one system may exert corresponding effects on another system, which exacerbates the pathophysiology of FC[30,31].

The association between GBA dysregulation and FC

The pathophysiology of FC has been linked to dysregulation of the GBA. According to previous studies, individuals with FC frequently demonstrate changes in the composition of the gut microbiota, which are exemplified by decreases in beneficial bacteria such as Lactobacillus and Bifidobacterium, as well as an increase in possibly pathogenic species. Reduced SCFA production may result from this dysbiosis, due to the fact that it is necessary to maintain a healthy and motile gut. Furthermore, changes in the microbiota may affect signaling pathways that are important for intestinal-brain connections and cause decreased motility and increased visceral hypersensitivity. Due to the fact that psychological factors, including anxiety and depression, can worsen gut symptoms and change the motility of the intestine, they are also intimately related to FC via the GBA. For the purpose of successfully controlling FC, an increased focus on both psychological and microbiological imbalances is essential[30,32].

THE APPLICATION OF PROBIOTICS IN FC IN ELDERLY INDIVIDUALS

The application of probiotics in managing FC among elderly individuals is gaining recognition because of their potential to enhance gut health and improve bowel function. FC is prevalent in older adults and is often exacerbated by factors such as decreased physical activity, polypharmacy, and changes in diet. Probiotics, which are defined as live microorganisms that confer health benefits when consumed in adequate amounts, can help to restore the balance of the gut microbiota, which is frequently disrupted in this population. Various strains of probiotics (particularly those belonging to the genera Lactobacillus and Bifidobacterium) have been investigated for their ability to promote gut motility and alleviate constipation symptoms. The mechanisms through which probiotics exert their effects include enhancing intestinal barrier function, modulating the GBA, and producing SCFAs that stimulate colonic motility. In particular, the GBA is an area of interest because it highlights the interplay between the gut microbiota and neurological functions, thus suggesting that probiotics may also exert cognitive benefits in addition to their GI effects[33].

Types and mechanisms of probiotics

Probiotics encompass a variety of strains, with each strain exhibiting unique properties and mechanisms of action. The most commonly investigated strains for treating FC in elderly individuals include Lactobacillus rhamnosus, Bifidobacterium lactis, and Lactobacillus casei. These strains have been shown to improve bowel regularity by increasing the production of SCFAs, which are critical for gut motility. SCFAs, such as butyrate, are produced via the fermentation of dietary fibers by gut bacteria and play a significant role in maintaining colonic health. Additionally, probiotics can influence gut motility by modulating the levels of neurotransmitters, particularly serotonin, which is known to affect gut peristalsis. The competitive exclusion of pathogenic bacteria by probiotics also contributes to a healthier gut environment, thereby reducing inflammation and promoting a balanced microbiome. Furthermore, certain probiotics have been observed to increase the frequency of bowel movements and improve stool consistency, thus making them a viable option for managing constipation in older adults[33,34].

Overview of clinical research results

Valid results have been obtained from clinical investigations examining the efficacy of probiotics in treating FC in elderly individuals. For example, in a randomized controlled trial[33], the frequency and consistency of stool were shown to be considerably better with the use of a multistrain probiotic formulation compared to the use of a placebo over the course of 12 weeks. The study revealed a cumulative effect of prolonged probiotic use, as evidenced by the significant increase in bowel movements observed in participants receiving probiotics, especially after the 71^st day of treatment. Probiotics were shown to not only increase the frequency of bowel movements but also improve the general health of older individuals with respect to of their condition, according to another meta-analysis[34] that involved several clinical trials. However, it is important to consider that although many studies have reported optimal results, more research is needed to determine standard guidelines for the use of probiotics in this population because of the various probiotic formulations that can be used, as well as the lengths of treatment[35,36]. Table 1 lists the randomized clinical trials of clinically proven therapeutic effects on FC in the elderly individuals with probiotics[33,36-40].

Table 1 Summary of randomized clinical trials on probiotics in the treatment of functional constipation in the elderly individuals.

Ref.	Country	Probiotic strain(s)	Inter-vention time	Study population	Outcomes
Ouwehand et al[37], 2002	Finland	Lactobacillus rhamnosus and Propionibacterium freudenreichii	4 weeks	Elderly subjects (n = 28)	Some relief from constipation may be observed with the combination of 2 probiotics
Ghafar et al[38], 2020	Malaysia	MCP® BCMC® strains	7 days	FC patients 60 years or older (n = 72)	Stool frequency and consistency were improved following the administration of probiotics
Ibrahim et al[39], 2020	Malaysia	MCP® BCMC® strains	8 weeks	Parkinson's disease patients with constipation (n = 48)	Probiotics improved bowel opening frequency and whole gut transit time in Parkinson's disease patients with constipation
Matsuura et al[36], 2021	Japan	Lactomin preparation	12 weeks	FC patients 65 years or older (n = 30)	There was a significant improvement when probiotics were administered
Šola et al[33], 2022	Croatia	Bifidobacterium animalis subsp. lactis BLC1, Lactobacillus acidophilus LA3 and Lactobacillus casei BGP93	12 weeks	60 participants aged 77.9 years ± 8.84 years with FC	Multistrain probiotics were shown to increase the frequency of bowel movements
Takeda et al[40], 2023	Japan	Bifidobacterium longum BB536	4 weeks	79 FC patients (mean age of 77.9 years)	Probiotic supplementation significantly improved bowel movements

FC: Functional constipation.

Safety and tolerability of probiotics

The safety and tolerability of probiotics in the elderly population have been extensively evaluated, with most studies reporting favorable outcomes. Probiotics are generally well tolerated, with few adverse effects being noted, thus making them safe adjunctive treatments for FC.

Clinical trials have shown that multistrain probiotics do not significantly alter laboratory blood parameters or cause any serious side effects, which is particularly important in older adults who may have comorbidities and who are often prescribed multiple medications. Safety assessments of specific strains, such as Lactobacillus plantarum and Bifidobacterium animal strains, have confirmed their nonvirulence and lack of antibiotic resistance genes, thus further supporting their use in clinical practice. However, it is crucial for health care providers to monitor individual responses to probiotics, as some patients may initially experience mild GI discomfort. Overall, the evidence suggests that probiotics can be safely integrated into the management plan for elderly patients who are suffering from FC, thus contributing to improved quality of life without significant risks[35,36].

THE APPLICATION OF PREBIOTICS IN FC IN ELDERLY INDIVIDUALS

Definition and function of prebiotics

Prebiotics are defined as nondigestible food ingredients that selectively stimulate the growth and/or activity of beneficial bacteria in the colon, thereby improving host health. This definition has evolved to include substrates that confer health benefits beyond the gut, thereby also impacting extraintestinal tissues. Prebiotics function by serving as a food source for beneficial gut microorganisms, thereby leading to the production of SCFAs and other metabolites that play crucial roles in maintaining gut health and overall well-being. The most commonly investigated prebiotics include inulin, fructooligosaccharides, and galactooligosaccharides (GOSs), which have been shown to increase gut microbiota diversity and abundance. In the context of FC, which is prevalent among elderly individuals, prebiotics may help to alleviate symptoms by enhancing bowel regularity and stool consistency. The mechanism by which prebiotics exert their effects involves modulation of the gut microbiota, thus leading to increased microbial diversity and abundance of beneficial bacteria such as Bifidobacteria and Lactobacilli. These changes can result in improved intestinal motility and a reduction in constipation symptoms, thus making prebiotics a promising adjunctive therapy for elderly patients suffering from FC[41,42].

Basic research and clinical application prospects

Recent studies have highlighted the potential use of prebiotics in managing FC, particularly in the elderly population. Basic research has shown that prebiotics can significantly alter the composition of the gut microbiota, which is often dysregulated in individuals with constipation. For example, a systematic review indicated that prebiotic supplementation led to increased stool frequency and improved stool consistency in patients with FC[43]. Clinical trials have demonstrated that specific prebiotics, such as inulin and GOSs, can effectively enhance bowel function and reduce the severity of constipation symptoms in elderly individuals[44,45]. Additionally, the safety profile of prebiotics is generally considered to be good because of the small number of unfavorable effects that have been documented, which makes them appropriate for use in older individuals who may be more sensitive to pharmacological treatments over long-term periods of time. Moreover, the enhancement of GI health and increase in quality of life are two possible ways that prebiotics can be integrated into dietary therapies for elderly patients. To provide conclusive guidance regarding the best types, dosages, and combinations of prebiotics for this population, more extensive, high-quality clinical trials are needed[46,47]. Furthermore, according to clinical research, prebiotic supplementation can increase intestinal motility and the synthesis of SCFAs, which are essential for the health of the gut[48]. Furthermore, prebiotics decrease inflammation and modify the GBA, which may also be a contributing factor to the elderly population's ability to manage constipation[49]. Although there is some evidence to support the use of prebiotics, there are still issues that need to be addressed regarding this type of treatment, which can be achieved by creating standardized formulations and dosing regimens that are customized to the specific requirements of each individual. Future studies should focus on clarifying the particular ways in which prebiotics affect gut motility by examining how these ingredients function together with probiotics to treat FC. Furthermore, by investigating novel prebiotic chemicals that are derived from polyphenols or seaweed, therapeutic approaches that can be used to control constipation in older adults may also be developed[50,51]. Overall, the use of prebiotics in the management of FC in senior patients is a safe, natural, and efficient approach that aligns with current developments in the area of customized and dietary-based therapies in the field of health care.

CONCLUSION

In this study, we summarized the relationship between FC and the elderly population, as well as how this relationship with intestinal microbiota dysbiosis results in a very complicated scenario. In the last several years, this scenario has been intensively researched, thereby resulting in deeper knowledge regarding the underlying mechanism of FC in the GI tract in this age group, as well as the role of the gut microbiota in elderly individuals. This suggests that a change in the composition of the gut microflora may affect the tendency of the intestinal microbiota to cause constipation and increase the frequency of symptoms in the GI tract; therefore, changes in the intestinal microflora tend to aggravate these symptoms. Moreover, the regulation of constipation by the intestinal-brain axis cannot be enhanced by the contribution of the latter factor. As the CNS functions in this reciprocal communication pathway with the GI tract, along with the fact that the CNS is important in modulating the sense of discomfort and regulation of gut motility, the issues of constipation have been considered to be a result of both local intestinal problems and systemic problems that are dependent on neurophysiological variables. These data indicate the possible use of probiotics and prebiotics as intervention approaches, which represents a valuable area of research in the field of medicine. Moreover, with respect to the use of prebiotics and probiotics as interventions, the effects of these treatments can be examined in the investigation of various diseases, including expected benefits of these treatments with respect to symptom resolution of constipation in older age groups. However, although there is some indication that these interventions have demonstrated beneficial effects, there is still a need to determine the potential factors and side effects associated with prebiotics and probiotics, as well as their optimal doses. Furthermore, the long-term safety/efficacy and effect of these therapies should also be determined.

Future studies should use a multidisciplinary approach that incorporates microbiology, neurology, and gerontology to create comprehensive management plans for FC. By balancing various research viewpoints and findings, we may encourage a more holistic understanding of this situation, thus providing an avenue for new treatment alternatives that not only ease symptoms but also increase the quality of life for elderly patients. Moreover, the encouragement of collaboration among researchers, clinicians, and industry stakeholders will be critical in translating these findings into clinical practice, thereby eventually leading to improved patient outcomes and a better understanding of the complicated interplay between gut health and overall well-being in the aging population.