Novel Approaches to Prevention and Treatment of Age-Related Declines

#### **Chapter 6**

## Perspective Chapter: The Role of Modifiable Factors, Particularly Nutritional Factors, on Age-Related Sarcopenia

*Nafiseh Shokri-Mashhadi*

#### **Abstract**

Advances in medicine result in an increase in the age of global population. The percentage of people over 60 years will approximately be duplicated up to 22 between 2015 and 2050, which is associated with a notable rise in age-related complications such as sarcopenia and frailty. The age-related sarcopenia is defined by low muscle strength, and it is considered severe if low muscle strength, low muscle mass, and low physical performance are detected.This condition is associated with poor quality of life, risk of falls, fractures, and higher healthcare costs. Despite the growing interest regarding the treatment of this phenomenon, the lack of adequate knowledge underlying the multifactorial parthenogenesis of age-related sarcopenia hinders the diagnosis of effective therapeutic approaches. In this respect, one of the major solutions would be to recognize the effect of modifiable factors on muscle health during the lifetime. Previous observations indicated that dietary and nutritional factors, beyond other environmental agents across the life course are related to muscle mass and function in the elderly. With respect to the fundamental role of nutrients with antioxidants properties in maintaining many aspects of health, this chapter aims to discuss the association between components of sarcopenia and nutritional status in older adults, and their potential effect on prevention and treatment of age-related sarcopenia.

**Keywords:** age-related sarcopenia, nutritional factors, prevention, treatment, dietary quality

#### **1. Introduction**

#### **1.1 Definition of sarcopenia**

The average age of populations is increasing because of numerous factors, including advances in medical care and decreasing birth rate [1, 2]. The percentage of people over 60 years will approximately be duplicated up to 22 between 2015 and 2050, which is associated with a notable rise in age-related complications such as sarcopenia and frailty [3]. Definitions of age-related sarcopenia have evolved over time in an

attempt to better characterize sarcopenia. The name for this phenomenon derives from the Greek term sarx (flesh) and penia (loss) [4]. Early definitions of sarcopenia were based exclusively on an age-related reduction in muscle mass [5]. However, the two-dimensional nature of these conditions (muscle mass loss and muscle strength loss) suggests that both its quantitative and qualitative range should be evaluated [6]. Therefore, the European Working Group on Sarcopenia in Older People (EWGSOP) described sarcopenia as an age-associated decline in muscle mass and strength with functional impairment [7].

Beyond the loss of muscle tissue that occurs over a lifetime, this condition is also associated with the conversion of type II fibers to type I fibers, which results in impairment of muscle quality and muscle function [8].

Categorizing sarcopenia into pre-sarcopenia, sarcopenia, and severe sarcopenia has also been defined by the EWGSOP that suggested the pre-sarcopenia stage as low muscle mass with no impact on muscle strength or physical performance, whereas the sarcopenia stage distinguished as low muscle mass with either low muscle strength or low physical performance and severe sarcopenia as the presence of all three criteria [9]. While interest in sarcopenia has risen in recent years, contention still exists over most components of the disease, with a universally accepted definition still lacking.

#### **1.2 Diagnosis of sarcopenia**

Various approaches can be used to assess muscle mass. Current assessment tools include body imaging techniques, bioelectric impedance analysis, anthropometric parameters, and biochemical markers [10].

Computed tomography (CT) and magnetic resonance imaging are able to effectively distinguish fat from other soft tissues, which makes these presently the gold standard method for the assessment of body composition. However, limited access, the high cost, and the risk of radiation inhibit the use of these techniques in clinical practice [11]. Therefore, dual-energy X-ray absorptiometry (DXA) is the most popular method for correctly evaluating body composition and widely used to assess muscle mass in research studies due to speed of measurement and relatively low per patient scan cost with typically low radiation [12]. Though, seeking for inexpensive, easy-to-use, and derived measures methods such as phase angle causes the application of bioimpedance technology. Nevertheless, using the estimation of body composition and muscle mass through anthropometric measurements, such as mid-upper arm circumference, calf circumference, and skinfold thickness, may allow us initially assess sarcopenia in situations that imaging equipment is typically unavailable in primary care settings [13].

The defining cutoff point for the identification of muscle loss depends upon the measurement technique chosen and the availability of reference studies. Low muscle mass is usually distinguished by a skeletal muscle mass index ranging from 7.23 kg/ m2 to 8.87 kg/m2 in men and 5.45 kg/m2 to 6.42 kg/m2 in women [14]. Moreover, it is generally accepted that low physical performance is defined as a gait speed of less than 0.8 m/sec [15] and low muscle strength is usually defined by handgrip strength of less than 30 kg for men and less than 20 kg for women [7]. Nevertheless, the quadriceps strength cut-off points of 18.0 kg for older men and 16.0 kg for older women proposed as a muscle strength measurement for sarcopenia diagnosis in older Asian people [16].

Because of this diversity in the cutoffs of the sarcopenia's characterization, EWGSOP has recommended that more research is urgently needed in order to obtain accurate reference values for different nations and countries around the world [17].

*Perspective Chapter: The Role of Modifiable Factors, Particularly Nutritional Factors... DOI: http://dx.doi.org/10.5772/intechopen.105433*

#### **1.3 Pathophysiology of and risk factors for sarcopenia**

The pathophysiology of sarcopenia is multifactorial. Several underlying mechanisms have been linked to the development of sarcopenia, although not all have been fully elucidated [6]. Prevalence of sarcopenia is mostly associated with chronic inflammation, which may lead to a vicious cycle of intricate interactions among risk factors [18]. However, research on sarcopenia prevention and treatment is developing quickly because of insufficient evidence for the underlying cellular mechanisms of the progress and maintenance of sarcopenia. So, it seems that understanding the factors related to increasing sarcopenia risk may provide strategies for intervention and disease improvement.

Inflammation in aging is one of the main suggested factors of sarcopenia characterized by a chronic progressive increase in pro-inflammatory cytokines, and the reduced serum level of anti-inflammatory cytokines [17]. Decline in immune function, plays an important role in several age-related diseases, for example Alzheimer's disease, Parkinson's disease, multiple sclerosis, atherosclerosis, and other complications [19, 20].

The majority of studies have demonstrated that inflammatory cytokines have an important effect on skeletal muscle wasting, leading to an imbalance between protein synthesis and catabolism [21]. It reasonably has shown that reduced rates of protein synthesis paralleled to increased protein breakdown in the skeletal muscle are associated with a variety of produced pro-inflammatory cytokines during the inflammatory response. Indeed, the effects of pro-inflammatory cytokines on muscle mass may be mediated by activating the transcription factor NF-κB in line with a production of ROS in the muscle of the elderly people [22, 23]. Additionally, we recently indicated that circulating levels of C-reactive protein (CRP) and hs-CRP are independently associated with impairment of muscle strength [24]. It is also suggested that low muscle strength is associated with the high levels of inflammatory cytokines [25] such as CRP [26]. These findings may suggest that the plasma concentration of some inflammatory molecules is related to the aspects of muscle decline and functional impairment.

Another suggested factor is Insulin resistance (IR) which is defined by reduced peripheral glucose utilization in skeletal muscle, majority of whole-body insulin-stimulated glucose disposal, that develops with age [27]. Various studies demonstrated that IR is related markedly to the different diagnostic components of sarcopenia [28]. Data on the prevalence of sarcopenia in Korean elderly men aged more than 65years recommended that higher IR and lower vitamin D levels are independently associated with the presence of sarcopenia in community-dwelling elderly men [29]. In another study conducted by Gorshunova et al., low muscle mass and muscle strength were significantly related to increased indices of IR, probably as a result of energy homeostasis disorders and the deterioration of glucose in the skeletal muscles [30]. One of the anticipated mechanisms of insulin resistance in elderly people is a reduction in the size of type II fibers which may reduce mitochondrial activity and result in IR in muscle [31, 32].

On the other hand, recent investigations illustrated that serum level of negative regulator of muscle growth, such as myostatin could increase with advancing age [33] and may play an important role in the resistance of insulin in muscles [34]. Moreover, aging skeletal muscle inflammation through activation of the classical signaling pathway also has impact on insulin uptake [35]. Furthermore, the effect of accumulation of intramyocellular lipid has been systematically evaluated and reported a wellestablished association between accumulation of intramyocellular lipid and muscle IR [30]. Finally, it is understood that strategies for identifying improvements and insulin sensitivity treatments can propose possible preventive measures against sarcopenia.

Aging is also related to changes in a several hormones status, including testosterone, estrogen, growth hormone, insulin-like growth factor 1, and corticosteroids [36], and the clinical significance of these deficiencies is variable with age [37]. It is previously supposed that the age-dependent decline in GH and IGF-1 levels is related to the pathogenesis of sarcopenia [38]. Moreover, in a recent observational cohort study, low baseline serum IGF-1 levels correlated with lower handgrip strength and worse physical performance [39]. Nevertheless, the impact of long-term GH therapy in the treatment of sarcopenia in elderly individuals with low GH/IGF-1 levels is still unclear. Cortisol is also the most potent immunosuppressive agent which can be stimulated by inflammation and therefore can be related to the development of sarcopenia and its components; muscle strength, muscle mass, and physical function. We could speculate from studies that the systemic overproduction of glucocorticoids during aging is associated with an increase of sarcopenia risk. However, further longitudinal studies are required to confirm these relationships.

In terms of modifiable risk factors, the relationship between adult lifestyle and sarcopenia has been highlighted in order to provide strategies for prevention of and improvement in age-related sarcopenia. In this concern, mental state, smoking, low body mass index (BMI), nutritional status, and physical activities have been introduced as the most potential changeable factors that could be applied in future strategies to prevent or delay the progression of sarcopenia [40–42]. The strong association between alteration in body composition in lifetime, namely fat-free mass, skeletal muscle mass, and BMI with prevalence and incidence of sarcopenia has been shown [43]. In addition, various previous reviews of studies revealed the relationship between physical inactivity and losses of muscle mass and strength [40], while resistance training was reported to have a beneficial effect on the physical performance measures in most studies [44, 45]. Regarding mental health, several studies found that sarcopenia is associated with cognitive decline and depression which could be due to some of the predisposing factors underlying sarcopenia, such as oxidative stress, inflammation, and insulin resistance [46]. Among them, one of the important modifiable factors in maintaining healthy status, in helping recovery from acute conditions, and in prevention of chronic diseases across lifespan is optimal nutritional status [47]. On the other hand, poor nutritional status is associated with several adverse consequences in community-dwelling older individuals, such as inflammation, cachexia, altered gut integrity, and muscle dysfunction [48, 49]. In addition, it is shown that the quality of the diet along with the lifetime has a close relationship with the sarcopenia [50]. It has been demonstrated that individuals consuming less energy will lose more muscle tissue. Therefore, avoiding under-nutrition is required to prevent muscle loss [47, 51]. Many nutrients have also been linked with the development of sarcopenia [47]. In this regard, the Korea National Health and Nutrition Examination Survey (KNHANES) cohort has revealed a lower energy, protein, and carbohydrate intake among sarcopenic older adults [52]. Given that evaluating the role of dietary nutrient intake in the treatment and development of sarcopenia would be valuable. Following we summarized studies in which the role of various nutritional factors on age-related sarcopenia was evaluated.

#### **2. Role of nutritional factors in prevention and treatment of sarcopenia**

#### **2.1 Role of dietary protein in prevention and treatment of sarcopenia**

The scientific literature indicated that the amount of daily protein intake is related to prevention of muscle functional decline and sarcopenia treatment, as older adults

*Perspective Chapter: The Role of Modifiable Factors, Particularly Nutritional Factors... DOI: http://dx.doi.org/10.5772/intechopen.105433*

have an increased need for dietary protein to stimulate their muscle protein synthesis [53, 54]. Furthermore, Sovianne et al., showed a significant difference in protein intake (gram/day) among sarcopenic and non-sarcopenic older adults [55]. It is supposed that lower energy requirements and reduced appetite decrease total energy consumption in aging, which can significantly reduce dietary intake of protein [56]. It proposed that dietary protein supplementation more than recommended dietary intake (above 0.8 g/kg/d) may have beneficial effect on sarcopenia [57, 58]. However, other recent studies have shown that muscle loss cannot be entirely stopped, even when daily protein intake is maintained at a high level [59]. So, the role of protein supplementation on age-related sarcopenia is somewhat controversial and might be affected by the nutritional status of individuals [60].

It is also worth noting that the type of protein ingested and timing of protein intake throughout the day could determine the amount of skeletal muscle mass [61]. In these regards,nutritional supplementation including 20 g whey protein and 800 IU vitamin D in previous randomized double blind research leads to further losses of intermuscular fat (*p* = .049) and increased normal muscle density (*p* = .018) after the 6-month intervention [62]. These results were also confirmed by another study [63]. However, a recent meta-analysis of eight studies (n = 557) conducted by Tieland et al., showed no significant positive effects of protein or amino acid supplementation on lean body mass, muscle strength, or handgrip. Nevertheless, it seems that there were various heterogeneities in included trials in the mentioned study, such as duration of treatment and type of supplementation, and dosage which could affect the result interpretation [64]. So, it can be concluded that this general lack of effect of protein supplements directed us to assess positive associations between protein intake and muscle mass and function through cohort studies.

The anabolic effects of some amino acids on muscle mass also have been investigated in several studies. Creatine, as one of the most important amino acids located primarily in muscle tissue, accelerates muscle ATP regeneration throughout the increased energy demand [65, 66]. In this aera, the increased muscle mass and muscle strength with exercises and an additional effect of creatine were found in clinical trials [67]. Moreover, increased physical performance with exercises and an interactive effect of creatine were observed in some studies [68]. Results of a previous metaanalyses specified that creatine supplementation combined with resistance training could have a positive effect on aging muscle mass and upper body strength compared to resistance training alone [69]. In agreement with these findings, the recent metaanalyses also showed that creatine supplementation leads to greater increases in muscle mass (SMD: 1.37 kg [95% CI = 0.97–1.76]) and leg muscle strength (SMD: 0.24 kg [95% CI = 0.05–0.43]) in participants with a mean age of 57–70 years [70]. The molecular mechanisms underlying the improved protein synthesis and muscle strength following creatine administration might be correlated with an increase in skeletal muscle phosphocreatine content and enhanced muscle glycogen storage through exercise [67]. Despite these promising results, it is worth to mention that the vast majority of these studies measured the impact of combined exercise interventions and creatine supplementation in the sarcopenic populations suffering from malnutrition [69].

#### **2.2 Role of n-3 fatty acids in prevention and treatment of sarcopenia**

Many nutrients also have anabolic effects on aging musculoskeletal health. There is growing evidence for an association between n-3 fatty acids intake alone or in

combination of other nutrients and components of sarcopenia, including muscle mass, muscle strength, and physical performance [71, 72]. In this regard, the investigation of possible relationship between circulating *n*-3 FA levels and sarcopenia among 125 participants in Asian older adults indicated that subjects with low muscle strength had 32.4% lower serum *n*-3 concentrations (*P* = 0.030) than controls [73]. In addition, omega-3 fatty acids intake was lower in elderly sarcopenic patients than elderly subjects without sarcopenia [2.6 ± 1.0 vs. 3.0 ± 1.2 kcal/day, p = 0.046] [74].

Furthermore, the recent results of the Maastricht Sarcopenia Study also showed that sarcopenic older adults had a 10–18% lower intake of five nutrients (n-3 fatty acids, vitamin B6, folic acid, vitamin E, magnesium) compared with non-sarcopenic older adults (*P* < .05) [55]. Similarly, prolonged supplementation with omega-3 fatty acids has been examined in older adults in order to improve the muscle protein synthetic response [75, 76], and importantly, the combined supplements providing high-quality proteins, leucine, vitamin D, and omega-3 fatty acids all together appear to be most favorable effects in the prevention of sarcopenia, while also being safe [77]. The positive effects of omega-3 fatty acids supplementation on muscle mass and function have also been identified by a systematic review and meta-analysis [72]. In addition, some studies specified that vitamin D supplementation combined with n-3 fatty acids, in particular EPA + DHA, may have favorable effect on physical function, muscle mass, and strength [77]. It is supposed that the anti-inflammatory effects of omega-3 fatty acids have an important role in the reduction in sarcopenia risk [78]. Nevertheless, the exact mechanisms by which n-3 fatty acids apply their beneficial effects on components of sarcopenia remain to be elucidated.

#### **2.3 Role of vitamin D in prevention and treatment of sarcopenia**

Among several nutrients, there has been increasing interest in the implications of vitamin D, either as single supplements or in combination with other supplements, for improving the physical function of older adults due to high prevalence of vitamin D deficiency [79]. A positive correlation between serum 25(OH)D concentration and muscle function has been shown [80]. The previous systematic reviews aimed at examining the benefits of vitamin D supplementation on sarcopenia in aging indicated the importance of considering baseline serum 25(OH)D concentrations in the response to supplementation [81]. While, concerning this issue, the recent meta-analysis of RCTs (2017) confirmed a slight improvement in the physical performance test following supplementation, no overall increase in handgrip strength was detected [82]. Nevertheless, this finding strengthens that vitamin D with a range of 800–1000 IU/day, but not necessarily at higher doses, has beneficial effect on muscle strength [77].

#### **2.4 Role of gut microbiota in prevention and treatment of sarcopenia**

Epidemiologic studies point out that altered gut microbiota structure according to diet, taking drugs, and other environmental factors across the lifespan result in different microbiota patterns, composition, and function in the elderly [83, 84]. The gut microbiota has the essential function maintaining some aspects of health [85]. Changing microbiota patterns are associated with significant changes in metabolic and physiologic regulation, and markers of inflammation that could result in agerelated adverse health consequences [86, 87]. Recent researchers have postulated that gut microbiota composition may have a great relationship with age-related alterations *Perspective Chapter: The Role of Modifiable Factors, Particularly Nutritional Factors... DOI: http://dx.doi.org/10.5772/intechopen.105433*

in skeletal muscle function [87]. In this concern, experimental studies revealed that changes in the gut composition via probiotic/prebiotic administration could influence muscle function and inflammatory status [88–90]. Our recent meta-analysis emphasized that probiotic supplementation for more than 12 weeks has positive impact on the muscle strength. However, the clear mechanism underlying the positive effect of probiotic administration on muscle strength was not identified. The possible explanation for these findings may be related to reduced levels of IGF-1 (insulin-like growth factor 1) during lifetime [39, 91]. The beneficial probiotic effects on circulating inflammatory biomarkers could be another description [92].

#### **2.5 Role of dietary quality in prevention of sarcopenia**

Research on dietary quality and dietary patterns has recently been undertaken to better understand the effects of diet as a whole and its impact on aging health complication such as sarcopenia. Results of recent cross-sectional study in 250 menopausal women 45 years old or older found that Mediterranean dietary pattern has a favorable role in the prevention of sarcopenia [93]. Additionally, adherence to dietary pattern including "vegetables-fruits" was associated with lower odds of prevalent sarcopenia in Chinese older men [94]. Furthermore, it is shown that subjects with higher consumption of "snacks-drinks-milk products" score had lower odds of sarcopenia (OR = 0.41, 95% CI: 0.24–0.70, *P*trend < 0.001) [94]. Interestingly, findings of recent cross-sectional study revealed that adherence to the Western dietary pattern, characterized by a high intake of sugar, soy, and fast foods, was not linked to sarcopenia (OR = 0.51; 95% CI: 0.21–1.24; *P*trend = 0.13) [95]. The link between healthier diets and physical performance among older adults has been proposed [41]. However, there is not enough research evidence available in various communities to inform about the definitive decision on the specific food pattern for the prevention or treatment of sarcopenia.

#### **3. Conclusion**

Age-related sarcopenia is a phenomenon with significant disability among the elderly. This condition is one of the most important public health problems among the healthy community. While there are the various notable bodies of research in order to define sarcopenia, the diversity in the cutoffs of the sarcopenia's characterization revealed the needs for more research to define accurate reference values in different nations and countries around the world. On the other hand, one of the main controversial topics in evaluating the influence of nutrition on age-related sarcopenia is related to various definitions of sarcopenia in different nations and countries. In addition, due to the lack of a valid biomarker for the detection of sarcopenia, the exact mechanism underlying beneficial effect of numerous nutritional factors on components of sarcopenia remains unknown. Furthermore, there is not enough research evidence available in various communities to inform about the definitive decision on the food for the prevention or treatment of sarcopenia. The other limitation of included studies in this review was connected to absence of information about dietary intakes and serum concentrations of many micronutrients in older adults. So, considering the biochemical levels and dietary intakes of micronutrients in future studies is recommended. Finally, further studies are needed to investigate the interaction effect of modifiable risk factors, in particularly nutrition over time based in the near future.

Overall, present findings from the scientific literature specified that the combined nutritional supplements, such as vitamin D, n-3 fatty acids, and creatine along with resistance training could have better improvement in aging muscle mass and upper body strength compared with each alone. This effect particularly was shown in subjects with low serum vitamin D concentrations. In addition, it seems that the beneficial effect of probiotic/prebiotic administration also depends on changed gut microbiota composition. It is worth to mention that adherence to healthy dietary pattern with high quality including vegetables and fruits may lead to lower odds of sarcopenia.

### **Conflict of interest**

None.

### **Author details**

Nafiseh Shokri-Mashhadi Food Security Research Center and Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran

\*Address all correspondence to: nafiseh.shokri@yahoo.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Perspective Chapter: The Role of Modifiable Factors, Particularly Nutritional Factors... DOI: http://dx.doi.org/10.5772/intechopen.105433*

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#### **Chapter 7**

## Perspective Chapter: Nutraceuticals as a Therapeutic Promise in Healthy Aging and Neurocognitive Disorders

*Abhishek Ramesh and Debanjan Banerjee*

#### **Abstract**

The world is facing a rapid population ageing. Noncommunicable disorders (NCDs) form the bulk of present-day morbidity. Besides dealing with neurodegeneration and neurocognitive disorders, modern-day therapeutics have also geared toward healthy ageing and preventive approaches. Several chemical substances belonging to classes of natural dietary origin display protective properties against some age-related diseases, including neurodegenerative ones. These compounds, known as nutraceuticals, differ structurally, acting on different pathways. There has been a paradigm shift in the understanding of dementias toward neuroinflammation, oxidative stress, immunomodulation, and gut-brain axis dysregulation. This offers promise for the nutraceuticals as a novel approach in the field of neurocognitive disorders and healthy ageing. However, the collective evidence is still evolving and as of yet not robust enough for nutraceuticals to be a part of clinical guidelines. The other caveats are lack of subjective understanding of use, and individual constituents of a product showing differential effects, which lead to ambiguous outcomes in clinical trials. This chapter critically looks at the role of various nutraceuticals in promoting healthy aging and management of neurodegenerative conditions (especially Alzheimer's disease). The evidence so far is highlighted with the challenges in their use and future directions of research.

**Keywords:** neurocognition, neurocognitive disorders, healthy aging, nutraceuticals, dietary natural products, neuroprotection, dementia

#### **1. Introduction**

Aging can be defined as the time-related deterioration of the physiological functions necessary for survival and fertility. It affects all the individuals of a species [1]. Age is a major risk factor for numerous illnesses, such as diabetes and cancer, various degenerative diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PDs), and various other neurocognitive disorders (NCDs) [2]. However, genetics, lifestyle patterns, environment,

and ecology play an equal or perhaps more important role in these diseases. Different biological theories have been put forward to explain the aging phenomena. Some of these are oxidative damage theory, general wear and tear theory, genetic instability, telomere shortening, mitochondrial genome damage, genetic program theory, etc. [1, 3–10].

Cognition is the higher order brain function that alters with advancing age, which, in turn, influences the quality of life of an individual [11]. Cognitive aging is governed by the interplay of multiple factors, including lifestyle, diet, nutrition, endocrine and genetic parameters, oxidative damage, neurotoxic exposures, and medical and surgical interventions for disease [12, 13]. Nutritional status plays a critical role in the cognitive abilities of an individual. It is a modifier of cognitive aging. Studies have shown that nutritional imbalance adversely affects the structural and functional integrity of the brain critically impacting the cognitive capacities and process of aging [14].

Older people are at risk for various micronutrient deficiencies due to social, physical, economic, and emotional factors. The development of effective nutritional interventions for promoting healthy aging and preventing and treating NCDs is an emerging and challenging area of biomedical research [13].

The term "nutraceutical" was originally defined by Stephen L. DeFelice, as a combination of terms *"nutrition and pharmaceutical* [15]." As per the European Nutraceutical Association, they are defined as *"naturally derived bioactive compounds that are found in foods, dietary supplements, and herbal products, and have healthpromoting, disease-preventing, or medicinal properties* [16]." On the other hand, "nutritional supplements" are nutritional compounds that supplement one's diet by increasing total daily intake [17]. Nutraceuticals are intended to affect the structure and function of the body; however, they do not undergo premarket approval. These are perceived as safe and less likely to have adverse effects [18]. Nutraceutical categories include dietary supplements (e.g., vitamins, minerals, coenzyme Q, carnitine, and botanicals such as ginseng and ginkgo biloba), medicinal foods (e.g., transgenic plants), and functional foods (e.g., oats, bran, omega-3 fatty acids, and plant sterols) [15, 19].

*"Nutritional psychiatry"* is a distinct field of psychiatry that studies the role and impact of diet and various nutraceuticals in the treatment and prevention of a range of psychiatric disorders, including neurocognitive disorders (NCDs) [20–22].

The role of nutraceuticals in noncommunicable diseases and healthy aging has been increasingly studied. Though the evidence base for their use in neurocognitive disorders has been increasing, guidelines regulating their use, safety, adverse effects, and efficacy in clinical settings are ambiguous and limited. There is a general tendency to accept "nutraceutical products" as a part of nutritional supplements in healthy aging with an "assumption" of their safety; however, more research is needed in the field [17, 18]. The ambiguity in evidence makes it challenging for clinicians working in the field of neuropsychiatry to take a clear stand related to their use and effectiveness. Keeping this in background, this chapter provides an overview of various nutraceuticals used in healthy aging and neurocognitive disorders, summarizes the available evidence base for the same, discusses the possible mechanisms of action, and outlines the challenges involved in their clinical use. This chapter is expected to stimulate thoughts and further research into this promising area that can offer viable solutions in the field of neurocognition.

### **2. Types of nutraceuticals that have been studied in NCDs and healthy aging**

#### **2.1 Mechanism of action: how do nutraceuticals intervene?**

The majority of nutraceuticals act as antioxidant agents; few of them are antiinflammatory, anticarcinogenic, and antiangiogenic agents (**Table 1**) [13, 35]. The


#### **Table 1.**

*Various nutraceuticals (and their sources) that have been studied in healthy aging and NCDs.*

various ways in which they act on cognitive processes and aging are depicted in **Figure 1**. However, these are only basics, and further research is necessary to elucidate the deeper underlying mechanisms.

#### *2.1.1 Effects of nutraceuticals in cognitive aging and progression to neurodegenerative disorders*

Cognitive changes associated with normal aging when accelerated result in mild cognitive impairment (MCI), characterized by structural changes in the brain such as amyloid plaque deposition, demyelination, and neurodegeneration. MCI increases the risk for developing major neurocognitive disorders through increased pathology, which results in marked cognitive impairment. Gene expression that has been altered with concomitant oxidative stress causes DNA damage and protein aggregation, which leads to MCI and dementia. Nutraceuticals of plant and animal origin help in the attainment of healthy aging and prevention and slow down the neurodegeneration process with increased longevity and preservation of cognitive abilities [36, 37]. Nutraceuticals have the potential to reverse structural changes in the brain, prevent DNA damage, and slow down protein aggregations promoting healthy aging as well as preventing or delaying the onset of MCI and dementia [13, 35, 38, 39]. Their effects on the cognitive changes in the pathophysiological spectrum are highlighted in **Figure 2**.

Both *in vivo* animal models and human studies in aging have shown that various nutraceuticals have a beneficial role in the promotion of positive mental health and well-being in aging, prevention of cognitive decline and eventually dementia, as well as slowing down the benign cognitive decline associated with normal aging [40–42]. Few nutraceuticals that were found to be useful in this regard are:

Brahmi herb (Bacopa monnieri): enhances cognitive performance in attention and logical memory domains and prevents and improves depressive symptoms.

Ashwagandha (Withania somnifera): enhances memory and sleep in aging and improves attention, executive functions, and information processing.

Turmeric (Curcuma longa): increases brain-derived neurotrophic factor (BDNF), prevents AD and depression.

Garlic (Allium sativum): reverses the levels of stress-related hormones and improves learning and memory.

Pumpkin seeds (Cucurbita maxima): improves memory and reduces depression [40].

Other nutraceuticals, including multivitamins, minerals such as zinc, selenium, and magnesium, fish oils, etc., also help in the improvement of cognitive functions in various domains [40, 43–47].

#### *2.1.2 Role of nutraceuticals in other neurocognitive disorders*

Most studies on the nutraceuticals' efficacy on neurocognitive disorders have focused on Alzheimer's disease. However, few studies have looked into the role of nutraceuticals in other neurocognitive disorders as well [39]. These studies are less robust and ambiguous in conclusive clinical implications.

In Parkinson's disease, nutraceuticals are found to be beneficial either by reducing the dose of L-dopa required or by acting independently, thus reducing the symptom severity [48]. *In vivo* studies have shown that vitamin B complex,

*Perspective Chapter: Nutraceuticals as a Therapeutic Promise in Healthy Aging... DOI: http://dx.doi.org/10.5772/intechopen.104932*

#### **Figure 1.**

*Mechanisms in which nutraceuticals act on cognition and neurocognitive disorders [35].*

#### **Figure 2.**

*Effect of nutraceuticals in mild cognitive impairment, neurocognitive disorders, and healthy aging.*

vitamin D, creatine, fish oils, curcuminoids, mucuna seed powder extract, resveratrol, quercetin, Ginkgo biloba, etc., are beneficial in reducing the severity of motor symptoms, preventing the nonmotor symptoms and cognitive symptoms associated with PD [49, 50].

In vascular dementia (VD), the B vitamin complexes especially vitamins B6, B9, and B12 are found to be useful in preventing its occurrence [51]. Various Chinese herbal preparations, such as Ginkgo, Huperzia, curcumins, Ginseng, Brahmi, saffron, green tea, etc., found to be helpful as adjuvants for the pharmacological treatment of cognitive decline in VD [52]. The complex herbal formulations that include these herbal products in various combinations were found to be superior to the individual preparation [53, 54].

In patients with stroke and post-stroke sequelae, nutraceuticals are found to be clinically beneficial at various stages. They reduce the risk of occurrence of stroke and can be used as prophylactic agents to promote ischemic tolerance to delay, prevent, or

postpone the occurrence or reoccurrence of stroke. They can also be used as adjunct therapeutic agents to minimize secondary brain damage in the case of acute stroke [55, 56]. Clinical studies have shown that vitamin B complex, vitamin E, magnesium, omega-3 fatty acids, polyphenols, and clinical studies have shown that coenzyme Q10, cystine, L-glutamate, retinoic acid, capsaicin, and vitamin D3 are useful as prophylactic agents. Nutraceuticals, including vitamin cocktail, minerals such as zinc and selenium, and curcumin, are used as therapeutic adjuvant agents in acute stroke for early recovery and prevention of complications [51, 56].

In Huntington's disease (HD), there are very few nutraceutical compounds that are found to be helpful. These include amino-oxy acetic acid (AOAA), levocarnitine [57], curcumin, taurine, resveratrol, anthocyanins, and quercetin [58]. Souvenaid™, a medical food composed of uridine monophosphate, DHA, choline, EPA, selenium, folic acid, phospholipids, and B vitamins has been found to have a significant positive impact on the behavioral symptomatology and theory of mind (ToM) skills in patients with frontotemporal dementia (FTD) [59].

#### *2.1.3 Molecular mechanism of action of nutraceuticals in invertebrate models*

Age is the major risk factor for various neurocognitive disorders [2]. There has been significant progress in elucidating the molecular mechanisms of aging [60, 61]. A number of genetic factors called longevity-related genes have been identified to modulate lifespan and health span in model organisms ranging from yeast, worms, flies, and rodents [62]. These genes fall into three nutrient sensing pathways:


Nutraceuticals bind to the proteins that are translated from these genes, which will either inhibit or stimulate the further downward molecular pathway, leading finally to longevity and increased health span (**Figure 3**).

#### *2.1.4 Interaction between nutraceuticals and the gut microbiota*

The gut microbiota is a collection of colonies of multiple microbes that reside in the body and live in a symbiotic relationship with their host [63]. The brain-gutmicrobiota axis comprises a part of this microbiota that is an extensive communication network between the brain [64] and gut. This axis plays an important role in the emotional and cognitive development of an individual, and any dysbiosis in this axis will lead to the occurrence of neuropsychiatric illnesses [65, 66]. Recent studies have shown the interaction between hypothalamo-pituitary–adrenal (HPA) axis and braingut-microbiota axis in the causation of psychiatric disorders [63].

Probiotics are various bacterial strains that exert beneficial effects through the number of ways such as antimicrobial effects, modulating the host's immune response, enhancing the functioning of epithelial barrier [63, 67]. The recent studies at the preliminary stage have shown that nutraceuticals, including prebiotics (fructooligosaccharides, xylo-oligosaccharides, and inulins), anthraquinones, phytoestrogens, polyphenols, amino acids, vitamins, and omega-3 fatty acids, can interact with

*Perspective Chapter: Nutraceuticals as a Therapeutic Promise in Healthy Aging... DOI: http://dx.doi.org/10.5772/intechopen.104932*

#### **Figure 3.**

*Schematic representation of nutrient signaling, and stress response pathways associated with aging and longevity in C. elegans and D. melanogaster [62]. ROS: Reactive oxygen species, SIR: Sirtuin, OSR: Osmotic stress resistant, MAPK: Mitogen activated protein kinase, UNC: Calcium/calmodulin dependent protein kinase, TOR: Target of rapamycin, SKN: Gene for protein skinhead-1, IIS: Insulin/IGF-1 like signaling, DAF: Gene for FOXO protein, HSF: Heat shock transcription factor.*

gut microbiota, often improving the diversity of gut microbiota, regulating immune function of the host, and improving the integrity of the intestinal barrier, which may have a beneficial role in the prevention and treatment of various neuropsychiatric and neurocognitive disorders [68–71].

#### **3. Evidence based on nutraceuticals in neurocognitive disorders and healthy aging**

There are a number of studies that have investigated the efficacy of nutraceuticals in the prevention and treatment of neurocognitive disorders. These studies vary from each other in terms of methodology, sampling size and strategies, study design, duration of treatment, and selection and doses of various nutraceuticals [72]. The results of all these studies are largely mixed. Therefore, these studies need to be replicated in larger

#### *Geriatric Medicine and Healthy Aging*


*Perspective Chapter: Nutraceuticals as a Therapeutic Promise in Healthy Aging... DOI: http://dx.doi.org/10.5772/intechopen.104932*


#### **Table 2.**

*An overview of few trials of nutraceuticals on various neurocognitive disorders, MCI, and healthy aging.*

representative samples for better quality of results and translation into routine clinical practice [73]. The lack of adequate blinding, placebo response, mixed population, and clinical pragmatism limit the interpretation of these results. Hence, it is difficult to draw clinical implications. The overview of some of the studies has been depicted in **Table 2**.

#### **4. Clinical utilities and advantages of nutraceuticals**

Recently, there have been various small- and medium-size studies looking into the efficacy of nutraceuticals in the promotion of healthy aging, prevention of dementia in MCI subjects, and slowing down the progression of cognitive deficits in various neurocognitive disorders. In comparison with the pharmacological drugs that are being used for dementia, nutraceuticals bear many advantages:


#### **5. Challenges and controversies of using nutraceuticals in clinical practice of dementia and healthy aging**

The use of nutraceuticals is not free from challenges. These range from the point of production to the point of consumption and its effects on the human body as well as lack of a sound evidence base. Especially, when it comes to the aging spectrum, it is challenging to set arbitrary standpoints to assess cognitive status and effects of nutraceuticals. Another age-old challenge is the lack of standardized socioculturally sensitive cognitive assessment tools. Nutraceuticals are widely available in food products and often used over-the-counter; hence, the dose–response relationship is often obscure. Various caveats while discussing the role of nutraceuticals in healthy aging and neurocognitive disorders are the following:


*Perspective Chapter: Nutraceuticals as a Therapeutic Promise in Healthy Aging... DOI: http://dx.doi.org/10.5772/intechopen.104932*

based on specific nutritional deficiencies is required in the current scenario of precision medicine practice [87].


status, cognitive and leisure-time activities, exercise, diet patterns, social connectivity, sleep, relationships, and stress levels). Many trials involving nutraceuticals either do not take these factors into account or are too stringent about inclusion criteria, which makes the study population nonrepresentative of clinical settings [73, 87]. This makes the findings difficult to interpret. The complex interplay between all these modifiable and nonmodifiable factors in aging can potentially modify the influence of nutraceuticals, which needs further research.

• There is a need for the development, implementation, and evaluation of public health strategies for improving nutrition in the general population [21].

#### **6. Conclusion and future direction**

Nutraceuticals are naturally derived bioactive compounds that are found in foods, dietary supplements, and herbal products and have health promoting, disease preventing, or medicinal properties. They have multiple actions, including antiinflammatory, antioxidant, anticarcinogenic, and antimicrobial properties. The field of nutraceutical psychiatry is relatively new and is slowly seeping into the mainstream psychiatric practice because of a number of recent studies that have established some efficacy in the prevention and treatment of neurocognitive disorders, slowing the progression of MCI into dementia and promotion of healthy aging. However, these studies are significantly heterogeneous in terms of methodology, sample selection, assessment, and dose and formulations of nutraceuticals with largely mixed results. We are lacking robust scientific evidence for the efficacy of nutraceuticals in cognitive neurology and psychiatry. Till date, nutraceuticals continue to be used as adjuvants or over-the-counter products for healthy aging as well as the prevention and management of dementia.

We need more large-sized randomized controlled trials for the better establishment of the efficacy of the nutraceuticals in neurocognitive disorders. The molecular basis of the action of nutraceuticals in human subjects needs to be unraveled for a better understanding of these molecules. The composition of each supplement must be carefully studied, and there has to be a rigorous regulatory mechanism for dosing, purification, mixing the different compounds, manufacturing, prescription, and marketing of these compounds that are backed by scientific evidence. Further studies are required for personalized medicine based on the physiological requirement of the body after testing for the blood levels of the nutraceuticals. From a public health perspective, the public and the health professionals need to be educated regarding the healthy nutrition and the availability of various nutraceuticals, and the policies pertaining to the regulation of sales of these compounds need to be formulated. Notwithstanding all limitations, nutraceuticals hold an immense promise in the field of healthy aging and disorders related to age. A deeper understanding of the nuances related to the mechanism of action, dosage, composition, role in different time periods of life, and, finally, other physiological effects will improvise their role in preventive and aging medicine. Age-appropriate guidelines can then be put into practice to help clinicians worldwide with their use. Whether nutraceuticals work in neurodegenerative conditions, especially dementia, stands the test of time, but based on the available evidence, it is definitely worth a try!

*Perspective Chapter: Nutraceuticals as a Therapeutic Promise in Healthy Aging... DOI: http://dx.doi.org/10.5772/intechopen.104932*

#### **Author contributions**

Both the authors have contributed equally to the conceptualization, design, literature review, drafting and editing the manuscript. The final version has been agreed upon by both the authors.

#### **Conflict of interest**

None.

### **Funding**

None to disclose.

### **Author details**

Abhishek Ramesh1 and Debanjan Banerjee2 \*

1 Department of Psychiatry, Adichunchanagiri Institute of Medical Sciences, Mandya, Karnataka, India

2 Consultant Geriatric Psychiatrist, ASHA THE HOPE, Kolkata, India

\*Address all correspondence to: dr.djan88@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 4
