Sirtuin 1 as a potential biomarker of undernutrition in the elderly: a narrative review

Abstract

Undernutrition and inflammatory processes are predictors of early mortality in the elderly and require a rapid and accurate diagnosis. Currently, there are laboratory markers for assessing nutritional status, but new markers are still being sought. Recent studies suggest that sirtuin 1 (SIRT1) has the potential to be a marker for undernutrition. This article summarizes available studies on the association of SIRT1 and undernutrition in older people. Possible associations between SIRT1 and the aging process, inflammation, and undernutrition in the elderly have been described. The literature suggests that low SIRT1 levels in the blood of older people may not be associated with physiological aging processes, but with an increased risk of severe undernutrition associated with inflammation and systemic metabolic changes.

Keywords:

• Adults
• malnutrition
• marker
• older
• sirtuin
• undernutrition

Introduction

According to global demographics, by 2050, there will be more people over 60 years of age than those under 15, and a total population of 2.1 billion compared to 901 million in 2015 (United Nations Department of Economic and Social Affairs, Population Division 2022). The aging of the population is associated with rising social costs, including the provision of adequate health services. Aging is a main risk factor for many serious diseases, including type 2 diabetes, cancer, cardiovascular, metabolic, neurodegenerative diseases, and malnutrition.

According to the European Society for Clinical Nutrition and Metabolism (ESPEN), the definition of malnutrition is unambiguous, open-ended and often used to describe undernutrition (Cederholm et al. 2015). “Malnutrition” or “undernutrition” are equally used both in the literature and in clinical practice, with a slight preponderance for malnutrition to describe the inadequate supply of energy and nutrients. In this article, the above terms are used equivalently. The risk of malnutrition increases with age (Russell and Elia 2011) and occurs in 27% of the population and 50% of people living in health facilities (Cereda et al. 2016). In the elderly, malnutrition may be associated with inadequate nutrient intake, leading to changes in body composition, which reduce physical and mental function and deteriorate clinical outcomes (Morley 2001). Malnutrition is accompanied by inflammation, which increases the need for energy and protein (Rondanelli et al. 2016).

Various causes of malnutrition in the elderly include nutritional disorders, gastrointestinal diseases, and impaired chewing due to poor or absent dentition. Aging is associated with a loss of organoleptic qualities, such as reduced taste and smell sensation, as well as reduced physical activity, which can significantly affect nutrient intake and lead to malnutrition with potentially serious health consequences (Hickson 2006).

The incidence of malnutrition is estimated to be 5.8% (Robberecht et al. 2019), while the risk of malnutrition may affect one third of elderly people (Kaiser et al. 2010). This risk increases when patients have difficulty performing basic tasks of daily life (Tamura et al. 2013). In addition, it carries an increased long-term risk, and individual nutritional support can reduce the risk of malnutrition (Hickson 2006).

Elderly people may experience frailty owing to chronic inflammation which may lead to the development of eating disorders. Symptoms of frailty are mainly sarcopenia, including loss of skeletal muscle mass, dysfunction of the neuroendocrine and immune systems, cognitive and motor disorders, and disturbances in energy regulation (Clegg et al. 2013). In the elderly, sarcopenia and inflammation frequently co-occur with malnutrition (Morley 2010; Volkert et al. 2019). In many studies, oxidative stress, central obesity, serum albumin (Wu et al. 2009), inflammation (Leng et al. 2002, 2004, 2007, 2009), 25-hydroxy vitamin D (Hirani et al. 2013), and vitamin E (Ble et al. 2006) have been used as parameters to identify malnutrition, sarcopenia, and frailty. Recent studies suggest a link between malnutrition in the elderly and Sirtuin 1 (SIRT1) (El Assar et al. 2018). This literature review aimed to investigate whether SIRT1 is associated with malnutrition and whether it can be used as a marker of malnutrition in the elderly, a population heavily affected.

Undernutrition

Criteria for diagnosing the risk of malnutrition

There are several criteria for diagnosing malnutrition. ESPEN distinguishes the following nutritional disorders: malnutrition, micronutrient abnormalities, and overnutrition (Cederholm et al. 2015). Malnutrition includes starvation-related weight loss, disease-related cachexia, frailty, and sarcopenia. The definition of malnutrition according to ESPEN is based on a decrease in body mass index (BMI) <18.5 kg/m² or unintentional weight loss >10% indefinitely or >5% in the past three months combined with a BMI < 20 kg/m² for those aged 70 years or <22 kg/m² for those aged ≥ 70 years or fat-free mass index < 15 and 17 kg/m² in women and men (Cederholm et al. 2015), respectively. The Global Leadership Initiative on Malnutrition (GLIM) developed in 2020 new diagnostic criteria for undernutrition, including three phenotypic and two etiological criteria (de van der Schueren et al. 2020). According to GLIM, the diagnosis of undernutrition requires at least one phenotypic and etiological criterion (Cederholm et al. 2019; Jensen et al. 2019).

If malnutrition is suspected, screening tools should be used to quickly assess its risk. There are several screening tools including the Mini-Nutritional Assessment (MNA) (Burns, Brayne, and Folstein 1998; Rubenstein et al. 2001; Vellas et al. 2006), the Nutrition Risk Screening (NRS-2002) (Liu, Zhang, et al. 2012), the Subjective Global Assessment Short Form (SGA) (Allard et al. 2020), and the Malnutrition Universal Screening Tool (MUST) The MNA is currently the most widely used screening tool for assessing malnutrition in older people. Donini et al. (2016) evaluated several screening tools, such as MNA, NRS-2002, and MUST, and revealed that MNA was the best tool for predicting survival in well-nourished older people in nursing homes. The procedures used for detecting malnutrition are presented in Table 1.

Table 1. Instruments to identify the risk of malnutrition.

1. Risk screening	Screening tools: MNA, NRS-2002, SGA, MUST
2. Diagnostic assesment ESPEN, GLIM	Etiological criteria for assessing the risk of malnutrition (one of the following): Reduced food intake or Inflammation/ disease burden Markers of inflammation (TNF alpha, IL-1, IL6, IL7, IL8, WBC, creatynine, albumine, prealbumins)
	Criteria for assessing the risk of phenotypic malnutrition (one of the following): Non-volitional weight loss >5% in the past 3 months combined with a Body Mass Index (BMI) <20 kg/m^2 in people under 70 years of age or BMI < 22 kg/m^2 in those over 70 years of age or FFMI < 15 and 17 kg/m^2 in men and women, respectively. >10% “indefinite time” Low BMI kg/m^2; BMI <18.5 kg/m^2 Low lean muscle mass
3. Diagnosis Criteria for the Diagnosis of Malnutrition	Must comply with: at least 1 phenotypic and 1 etiological criterion
4. Severity grading	Stage 1 (medium) and stage 2 (severe) according to the magnitude of changes in phenotypic criteria.
5. Dietary intervention	If oral food is possible (suitable passage through the gastrointestinal tract, no dysphagia) and/or If there is no improvement in nutritional status (persistent low muscle mass, nutritional parameters below normal) and/or not possible to meet > 60% of daily energy demand in a natural way Procedure: Referral to a nutritional clinic or hospital (Department of General Surgery, Internal Medicine, Gastroeneterology) In extreme cases (kachexia/kachexia) referral and urgent referral to the infirmary
6. Monitoring of nutritional status	Evaluation of the effectiveness of the nutrient supply in the feeding sheet General condition of the patient (heart rate, BP, respiratory tract performance, circulation, edema or dehydration characteristics, skin condition, presence of decubitus, Function of the digestive tract) Anthropometric parameters (body weight, arm circumference, calf circumference) expected weight gain 0.5–1 kg/^2 wk, if the gain is greater, there is a risk of overheating Laboratory parameters Functional parameters (muscular strength) Refeeding syndrome should be predicted

Authors’ own study, based on literature Allard et al. (2020); Burns, Brayne, and Folstein (1998); Cederholm et al. (2015); Cederholm et al. (2019); Donini et al. (2016); Jensen et al. (2019); Rubenstein et al. (2001); Vellas et al. (2006).

Laboratory indicators of nutritional status

The most important and common blood indicators used in the diagnosis of malnutrition include visceral proteins (Volpi et al. 2001), such as albumin, prealbumin, and retinol-binding protein, which are primarily synthesized in the liver. Low protein and energy intake, impaired liver synthesis, and inflammation in the body contribute to a decrease in visceral protein levels. Acute inflammation increases protein production, whereby the liver alters protein synthesis to reduce the synthesis of visceral proteins. In turn, the level of visceral protein correlates with the severity of the damage.

Although malnutrition is often associated with inflammation, the role of inflammatory biomarkers in malnutrition remains unclear. Above all, the biomarkers have low specificity and the presence of inflammation has a strong effect on visceral proteins in the serum. The uncertainty of the role of biomarkers is confirmed by the fact that their role has not been investigated in large randomized controlled studies (Cholewa et al. 2017).

Zhang et al. discussed the role of biomarkers in assessing the severity of malnutrition in the elderly and considered validated tools for assessing nutritional status (Zhang et al. 2017). They analyzed 111 observational and cohort studies with 52,911 participants from a variety of clinical settings. Biomarkers such as BMI and concentrations of albumin, hemoglobin, total cholesterol, prealbumin, and total protein among those at high risk of malnutrition assessed by MNA were significantly lower than those not at risk (p < .001). In the case of malnutrition, as determined by SGA and NRS 2002 in patients with acute illnesses, the predictive value of albumin and prealbumin was markedly reduced, leading to the conclusion that they are markers of inflammation rather than malnutrition. According to the authors, BMI, hemoglobin, and total cholesterol are useful markers of malnutrition in older adults.

The role of inflammation in the pathology of malnutrition

Inflammation plays a critical role in malnutrition pathophysiology. Weight loss is considered one of the most important criteria for malnutrition but disregarding other criteria may lead to an inappropriate diagnosis (Kirkland et al. 2013).

Inflammatory cytokines such as tumor necrosis factor-alpha (TNFα), Interleukin-1 (IL1), Interleukin-6 (IL6), serotonin, and gamma interferon play a significant role in the development of cachexia, as they stimulate the release of acute phase proteins, protein breakdown in muscle, and fat breakdown. The increase in pro-inflammatory cytokines is influenced by the progressive increase in glucocorticoids and catecholamines as well as by the decrease in growth and sex hormones. Studies suggest that systemic inflammation associated with TNFα production is involved in the mechanism of muscle mass loss and anorexia. In addition, this mechanism may occur during aging (Godoy et al. 1996).

Researchers have suggested that aging causes a pro-inflammatory response, which may be associated with a gradual decline in physical activity and initially manifests as chronic, low-grade inflammation (Crossland et al. 2010). In the development of inflammation, the source of inflammatory molecules appears to be fatty tissue (especially visceral fatty tissue), which contributes to the increased activation and infiltration of immune cells, especially macrophages and neutrophils. Activated macrophages can stimulate lipolysis in visceral adipose tissue and increase the concentration of circulating free fatty acids (FFA) by signaling TNF-α/Toll-like receptor-4. While increased levels of FFA amplify macrophages to increase secretion of important anti-inflammatory molecules (such as TNF-α, IL-1, and IL-6), these molecules also influence skeletal muscles, especially in those with a sedentary lifestyle. Increased levels of TNF-α, IL-6, and FFA appear to contribute to the activation of skeletal muscle proteolysis and insulin resistance, which are two major factors involved in different types of muscle atrophy. Degradation and reduction of the body proteins needed for the proper functioning of the organs, in favor of visceral proteins as an inflammatory reaction, gradually deteriorates the health of older people (Brocca et al. 2012). The occurrence of other comorbidities such as cancer or heart disease may contribute to the release of catabolic hormones such as cortisol, inflammatory cytokines, and increased reactive oxygen species (ROS). This process may be associated with the risk of malnutrition and concomitant sarcopenia (Crossland et al. 2008).

Chronic systemic inflammation is an important factor in both sarcopenia and malnutrition. If inflammation can be regulated by pro-inflammatory mediators, such as TNF-α, IL-1, and IL-6, malnutrition may be influenced. The pathway mediated by forkhead box 03 (FOX03), which activates the ubiquitin-proteasome system, is also involved in the inflammatory process, which primarily involves TNF-α and IL-6 (Sente et al. 2016). These cytokines may not only promote sarcopenia (Budui, Rossi, and Zamboni 2015) but also inflammatory malnutrition due to the interaction between inflammatory cells and organs, leading to reduced protein synthesis, increased protein breakdown, impairment of organ function, and the manifestation of clinical diseases associated with malnutrition (Jensen et al. 2010).

Inflammatory response in malnutrition

Malnutrition has been shown to be associated with inflammation (Bourke, Berkley, and Prendergast 2016). The proper development of the immune system is altered by malnutrition during critical periods in humans, including pregnancy, newborn puberty, and weaning (Keusch 2003; McDade et al. 2001). Chronic malnutrition and infection in children have been shown to weaken the immune response, leading to changes in immune cells and an increase in inflammatory mediators (Dülger et al. 2002). In addition, malnutrition in the early years of life increases the risk of chronic inflammation (Khoruts 2018; Latini et al. 2004; Martin-Gronert and Ozanne 2012), obesity (WHO 2004) (Swinburn et al. 2019), adverse metabolic alterations (Crispi, Miranda, and Gratacós 2018; Sommer et al. 2017), and intestinal dysfunction (Heijmans et al. 2008; Winick and Noble 1966) later in life.

The sirtuin family

Division and functions of sirtuins

Sirtuin proteins are involved in cellular processes, such as mitochondrial biosynthesis, lipid metabolism, apoptosis, cellular stress response, fatty acid oxidation, insulin secretion, and aging (Tanno et al. 2007). Eighteen different histone deacetylases (HDACs) have been identified in humans. HDACs are grouped into four classes (class I, II, III, and IV) and two families: classical and sirtuins (Gregoretti, Lee, and Goodson 2004). Sirtuins are a heterogeneous group of class III histone-nicotinamide adenine dinucleotide (NAD)-deacetylase-dependent enzymes that are not sequentially similar to the classic HDAC family but have a high sequence similarity to silent information regulator 2 (SIR2), originally discovered in the yeast Saccharomyces cerevisiae (Asher and Schibler 2011; Finkel, Deng, and Mostoslavsky 2009). Homologs of the yeast SIR2 gene have been detected in most organisms, including mammals (Haigis and Sinclair 2010). Seven isoforms of sirtuin, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7, have been identified in humans, which contain a conserved catalytic core domain composed of approximately 275 amino acids, except SIRT1 which is expressed. The sirtuins show different tissue specificities, target substrates, and cell localization (Price et al. 2012). A summary of all sirtuins, including the general distribution, the enzymes involved, and their locations, is given in Table 2.

Table 2. Division of sirtuins based on Manjula, Anuja, and Alcain (2020), Yan et al. (2018), Wu et al. (2018), Gao et al. (2018).

Form of sirtuin	SIRT1	SIRT2	SIRT3	SIRT4	SIRT5	SIRT6	SIRT7
Class	I	I	I	II	III	IV	IV
Enzymes, (Du et al. 2011; Rack et al. 2015)	Deacetylase	Deacetylase	Deacetylase	ADP-ribosyltransferases	Demalonylase, desuccinylase, deacetylase	Demalonylase, ADP-Ribosyltransferases depalmitoylase activity, deacetylase	Deacetylase
Location (Smith et al. 2000)	The nucleus and cytoplasm	The nucleus and cytoplasm	Mitochondria	Mitochondria	Mitochondria	The nucleus	The nucleus

SIRT1

SIRT1 is a nuclear protein that deacetylates transcription factors and cofactors that regulate metabolic pathways in the circadian rhythm and energy metabolism (Nakahata et al. 2008). SIRT1 plays key roles in aging, inflammation, gene silencing, apoptosis, and stress resistance (Chung et al. 2010; Rahman et al. 2012; Yao and Rahman 2012). These functions are mainly performed by the deacetylation of histones, transcription factors, or coactivators such as p53, forkhead box 0 (FOX0), nuclear factor αB (NF-αB), and coactivator 1α of the peroxisome proliferator-activated γ receptor (PGC-1α) and heterodimer Ku70 (Yao et al. 2012). The system-related biological functions of Sirtuin 1 are shown in Table 3.

Table 3. Biological functions of sirtuin 1 in the human body (authors’ own study).

Functions	SIRT1
Endocrine system	Regulates Adipocyte Differentiation and Adipogenesis (Zhou et al 2018) Regulates Lipid Metabolism in Skeletal Muscle (Zhou et al 2018)
Nervous system	the activation of SIRT1 is neuroprotective in AD*, PD*, and HD* neuroprotective roles in the CNS (Chandramowlishwaran et al. 2020), regulator of nutrient sensing in the neural circuits that govern central and peripheral networks (Tyagi et al. 2018)
Skeletal system	Loss of function: defect in skull formation and delay in mineralization (Cheng et al. 2003; Lemieux et al. 2005; McBurney et al. 2003) Gain of function: improved healthspan and increased bone mass (Herranz et al. 2010)
Reproductive system	Regulates inflammation, controls E-cadherin expression (Shirane et al. 2012), participates in activation of KRAS—Kirsten rat sarcoma virus in endometriosis (Yoo et al. 2017) Play a role as a tumor promoter and suppressor (Kratz et al. 2021) Assosiaction with fertility problems (Bódis et al. 2019) Endometriosis (Khazaei et al. 2019), polycystic ovary syndrome (Kiyak Caglayan et al. 2015), ovarian cancer (Qin et al. 2017), breast cancer (Santolla et al. 2015), endometrial cancer (Bartosch et al. 2016), uterine cancer (Tong et al. 2018)
Immune system	Sirtuins regulate the function of innate immune cells at multiple levels with important implications for immune and organismal aging. For the most part, sirtuin downregulation in human innate immune cells is associated with proinflammatory processes, and their overexpression is thought to protect tissues. Similarly, whole-body or myeloid-specific sirtuin deficiency in mice results in the development of different inflammatory conditions, including autoimmunity, obesity, and neurodegeneration (Lee et al. 2017; Lo Sasso et al. 2014; Pais et al. 2013; Schug et al. 2010)

*AD Alzheimer disease, PD Parkinson Disease, HD Huntington Disease.

Modulatory function of sirtuins

Studies have shown that molecules that activate sirtuins in humans can offer broad health benefits with strong anti-inflammatory, cardioprotective, neuroprotective, and anti-cancer effects (Kugel et al. 2016).

The therapeutic potential of increased SIRT1 activity in mammals has been demonstrated in animal models and in early clinical studies, making this enzyme an attractive drug target (Bonkowski and Sinclair 2016; Hubbard and Sinclair 2014). Therefore, the modulation of sirtuin activity may play an important role in the development of new therapies for age-related and metabolic diseases. Most sirtuin activators described concern SIRT1, inhibitors of SIRT1 and SIRT2, and of the least concern are SIRT3 and SIRT5 (Alcaín et al. 2010). The most effective substance, activating SIRT1 by more than 10 times, is resveratrol (3,5,4′-trihydroxystilben), a natural product of grapes and red wine (Gertz et al. 2012). In addition, a variety of synthetic resveratrol derivatives with changes at the B ring 4′ position may improve naturally occurring sirtuin activators and reduce toxicity to human cells, as well as increase the strength of SIRT1 activation and longer life in budding yeasts (Yang et al. 2007).

Reports have suggested that SIRT1 inhibitors and other sirtuin isoforms may also be useful (Chalkiadaki and Guarente 2015). Increasing advances in research and a growing number of structures of the sirtuin/inhibitor complex have aimed to develop potent and specific inhibitors targeting sirtuin (Schutkowski et al. 2014). Some pathophysiologies and sirtuin isoforms require inhibition rather than activation, for example, SIRT2 in neurodegenerative diseases (Donmez and Outeiro 2013). Studies have shown that inhibitors have the potential to be used as therapeutic drugs, including salermide, which inhibits the apoptosis of cancer cells, and suramine, an antiprotozoic agent. Sirtuin inhibitors are listed in Table 4.

Table 4. Sirtuin inhibitor compounds.

Sirtuin inhibitor compounds	Potential effect on health
Splitomicin (5690-03-9)*	Splitomicin is a small molecule inhibitor of Sir2p histone deacetylase activity, displaying higher activity in vivo (Hirao et al. 2003; Posakony et al. 2004)
HR73 (959571-93-8)*	HR-73 is a splitomycin derivative and a SIRT1 inhibitor. HR-73 induces p53 hyperacetylation and decreases HIV transcription (Elliott and Jirousek 2008; Weinberger and Shenk 2007).
Sirtinol (410536-97-9)*	Sirtinol is a cell-permeable inhibitor of sirtuin NAD^+-dependent deacetylases, inhibiting the yeast sirtuin Sir2p with an IC50 value of 68 μM and the human sirtuins SIRT1 and SIRT2 with IC50 values of 131 and 38 μM (Grozinger et al. 2001) Sirtinol inhibits the growth of cancer cells and suppresses inflammatory signaling in human dermal microvascular endothelial cells (Cea et al. 2011; Orecchia et al. 2011; Ota et al. 2006).
AGK2 (304896-28-4)*	AGK2 protects dopamine neurons from α-synuclein toxicity in both in vitro and in vivo Parkinson’s disease models, mimicking the effect of siRNA-mediated blockade of SIRT2 expression (Outeiro et al. 2007)
Cambinol (14513-15-6)*	Potential treatment of Gaucher disease and Parkinson’s disease: Cambinol, a sirtuin inhibitor, inhibits UDP-glucose ceramide glucosyltransferase (UGCG) activity, leading to a decrease in the cellular glucosylceramide (GlcCer) levels and an increase in cellular ceramide (the accumulation of GlcCer is associated with Gaucher disease and Parkinson’s disease) (Ishibashi, Ito, and Hirabayashi 2020)
Salermide (1105698-15-4)*	Cause tumor-specific apoptotic cell death (Liu, Su, et al. 2012) In MOLT4 leukemia cells, salermide causes 90% apoptosis within 72 h (IC50 ∼ 20 μM) by reactivating proapototic genes that are repressed by SIRT1 (Lara et al. 2009) Sirtuin inhibition significantly impaired acetylcholine-induced vasorelaxtion in aortas in trained rats (Harris, Hoffman, and Olesiak 2021)
Tenovin-1 (380315-80-0)* Tenovin-6 (1011301-29-3)*	Both compounds decreased tumor growth in vitro and delayed tumor growth in vivo without significant general toxicity (Lain et al. 2008)
Suramin (129-46-4)*	Polysulfonated naphthylurea with antiviral, antiparasitic, and anticancer activities (Wiedemar, Hauser, and Mäser 2020) reduces Zika virus infectivity in Vero cells (IC50 = ∼2.5-5 µg/mL) (Tan et al. 2017) In vivo, suramin induces cell cycle arrest at the G2/M phase and apoptosis in Leishmania donovani promastigotes in vitro and reduces hepatic parasitic burden in a mouse model of L. donovani-induced visceral leishmaniasis (Khanra et al. 2020) suramin (60 mg/kg) reduces tumor volume in patient-derived xenograft (PDX) mouse models of malignant mesothelioma (Chahinian et al. 1998) formulations containing suramin have been used in the treatment of African sleeping sickness (Chahinian et al. 1998)

Authors’ own study.

*CAS number (CAS - Chemical Abstracts Service).

Nutritional regulation of SIRT1 expression

The activity of sirtuins depends on the availability of NAD + and its precursors, such as niacin and nicotinamide, which stimulate sirtuins (Bleeker and Houtkooper 2016). To explain the mechanism regulating SIRT1 expression, a reference should be made to the complex reactions catalyzed by sirtuins, in which NAD + is degraded to nicotinamide and adenine. The effects of these enzymes require NAD + resynthesis, which occurs in two reactions. In the first reaction, catalyzed by nicotinamide phosphoribosyl transferase (NAMPT), phosphoribose binds to nicotinamide, resulting in nicotinamide mononucleotide. Subsequently, adenine binding catalyzes nicotinic acid mononucleotide adenyltransferase. Studies in mice have shown that the increase in NAD + levels is due to an increase in NAMPT activity (Revollo, Grimm, and Imai 2004). In other studies, the administration of NAMPT to young and older mice also increased the expression and activity of SIRT1 (de Picciotto et al. 2016).

Calorie restriction

Today, one of the best-described and proven factors to increase the sirtuin activity is the limitation of energy intake. However, the effects of the level of nutrient deficiency, duration, and type of organism studied on sirtuin levels remain unclear.

The natural and synthetic activators of sirtuins, their possible health effects, and their sources in food are summarized in Tables 5 and 6.

Table 5. Natural activators of sirtuins and their sources.

Compounds (Kim et al. 2016; Villalba and Alcaín 2012)	Potential effect on health	Source in food or origin of the substance
Natural activators of sirtuins
Resveratrol (501-36-0)*	Obesity treatment (Poulsen et al. 2013) Colon cancer prevention (Nguyen et al. 2009) Cardio protection (Decreases low-density lipoprotein [LDL] oxidation, and functions as a direct free radical scavenger) (Magyar et al. 2012)	Polyphenol that has been found in grapes, red vines (Jang et al. 1997)
Trans-ε-Viniferin (62218-08-0)*	Reduces production of reactive oxygen species (ROS), mitochondrial dysfunction, and PGC-1α depletion and increases protein levels and deacetylase activity of sirtuin 3 (SIRT3) in cells expressing mutant (Yu et al. 2018). Inclusion of trans-ε-viniferin in the diet reduces hepatic triglyceride accumulation and weight gain in a mouse model of diet-induced obesity (Ohara et al. 2015). Anti-inflammatory, antioxidant, platelet antiaggregatory and anticarcinogenic properties (Yáñez et al. 2006). Prevention of rotaviral diarrhea (Yu et al. 2018). Potential for the treatment of Alzheimer’s disease (Vion et al. 2018) Potential for the treatment of diabetes (Zhao et al. 2016).	Polyphenol that has been found in various red wines (Vitrac et al. 2005)
Vitexin (3681-93-4)*	Anticancer (Seyed et al. 2016), Anti-oxidant (He et al. 2016; Kim et al. 2005), Anti-inflammatory (Borghi et al. 2013; Choo et al. 2012; Flores et al. 2012; Galleano et al. 2012; Min et al. 2015; Rosa et al. 2016), Anti-neoplastic (Bhardwaj et al. 2015), Lifespan extending and stress resistant properties (Lee et al. 2015), Protective effects against endocrine and metabolic disease (Galleano et al. 2012; Schloms and Swart 2014), Anti-microbial and anti-viral effects (Krcatović et al. 2008; Quílez et al. 2010), Protective activity in cardiovascular system (Lu et al. 2013; Piccinelli et al. 2008), Protective effects against neurological and psychiatric diseases (Min et al. 2015; Song et al. 2003; Wang et al. 2015).	Found in the passion flower, Vitex agnus-castus (chaste tree or chasteberry), in the Phyllostachys nigra bamboo leaves, in the pearl millet (Pennisetum millet), and in Hawthorn, in amaranth, annual wild rice, barley, breakfast cereal, bulgur, common wheat, flour, hard wheat, millet, oat, oriental wheat, quinoa, red rice, rice, rye, sorghum, spelt, tartary buckwheat, teff, triticale, wheat, wild rice, black, tea, cocoa bean, common buckwheat, common oregano, common pea, common salsify, corn, cucumber, fenugreek, flaxseed, gram bean, green tea, herbal tea, mung bean, prairie turnip, red tea, sorrel, soy bean, sweet marjoram, tamarind tree fern (expected but not quantified) (Duke and Bogenschutz 1994; Shinbo et al. 2006).
Orientin (28608-75-5)*	Antioxidant and antiaging (Nayak and Devi 2005) Weight loss (Nagai et al. 2018) Anti-inflammatory (Sun et al. 2016) Anti-inflammatory agent (An et al. 2015; Bae 2015; Lee, Ku, and Bae 2014; Yoo et al. 2014) Antiviral and antibacterial agent (Boominathan et al. 2014; Lin et al. 2004) Anticancer effects (Nayak and Devi 2005) Protection against bone marrow damage (Nayak and Devi 2005; Uma Devi et al. 1999) Other (e.g., vasodilatation, anti-adipogenesis cardioprotective, neuroprotective, antidepressant-like, antinociceptive radioprotective effects) (Lam et al. 2016)	Orientin is a flavonoid isolated from Papaver orientale. Millets (Dykes and Rooney 2006) Buckaweat sprouts (Kim et al. 2008)
Fisetin (528-48-3)*	Antiaging and against cardiovascular disease (Currais et al. 2014; Zhu et al. 2017) Anticarcinogenic agent, chemopreventive/ chemotherapeutic agent against cancer (Lall, Adhami, and Mukhtar 2016; Syed et al. 2013) Antioxidant agent (Khan et al. 2013) Antidiabetic (Maher et al. 2011)	Flavonoid that has been found in various fruits and vegetables (Wang et al. 2006) found in strawberries (Maher, Akaishi, and Abe 2006)
Piceatannol (10083-24-6)*	Anticancer effects (Kwon et al. 2012; Seyed et al. 2016) Metabolic diseases (lowers lipid accumulation during late stages of differentiation) (Kershaw and Kim 2017) Cardiovascular diseases (lowers lipid and lipoprotein in vivo) (Rimando et al. 2005; Tang and Chan 2014) Also exhibits anti-proliferative and anti-inflammatory effects by inhibiting the activity of a wide range of tyrosine and serine/threonine protein kinases and suppressing NF-κB activation through inhibition of IκBα kinase (Ashikawa et al. 2002).	found in the skin of grapes and red wine as resweratrol analog formed by the cytochrome P450-catalyzed hydroxylation of resveratrol (Potter et al. 2002).
Quercetin (849061-97-8)*	Treatment of oral lichen planus (Amirchaghmaghi et al. 2015) Treatment of high blood pressure (Serban et al. 2016) Treatment of type 2 diabetes (improving the antioxidant status of patients with type 2 diabetes while having no other significant effect on glycemic control and lipid profil (Mazloom et al. 2014; Rezvan et al. 2017) Decreases the expression of TNF-α, IL-1β, IL-6, and IL-8 induced by PMACI in HMC-1 cells (Park et al. 2008) Cancer treatment (Ferry et al. 1996; Yuan et al. 2006) Treatment of colitis and gastric ulcer (Hamdy and Ibrahem 2010) Treatment of respiratory tract infection (Heinz et al. 2010)	flavonoid that has been isolated from a variety of fruits and vegetables (Calgarotto et al. 2018; Yuan et al. 2016). Found in apples, pears, onions and capers, has a stimulating effect expression of sirtuins in skeletal muscle, brain and liver (Davis et al. 2009; Kemelo et al. 2016)

Authors’ own study.

*CAS number.

Table 6. Synthetic activators of sirtuins.

Synthetic activators of sirtuins	Potential effect on health
SRT1720 (1001645-58-4)^∗	Extend lifespan in yeast and Caenorhabditis elegans in a manner that resembles caloric restriction. SRT 1720 is a selective small molecule activator of SIRT1 that is 1000-fold more potent than resveratrol. improves whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle, and liver In diet-induced obese and diabetic leptin-deficient mice, oral administration of 100 mg/kg SRT1720 once daily improves insulin sensitivity, lowers plasma glucose and increases mitochondrial capacity after 1 week of treatment (in Zucker fa/fa rats) (Milne et al. 2007)
Oxazolo [4,5-b] pyridines derivatives (273-97-2)*	Derivates were found to inhibit the proinflammatory mediators: TNF-a, IL-1b, and IL-6 ex vivo (Tantray et al. 2017)
Imidazo [1,2-b] thiazole derivatives (251-97-8)*	Activate the NAD^+-dependent deacetylase SIRT1, Potential new therapeutic target to treat various metabolic disorders, Potential of oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model (Vu et al. 2009)
1,4-dihydropyridine (DHP) derivatives (3337-17-5)*	Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells (Valente et al. 2016) Can inhibit tumor growth by promoting apoptosis in cancer cells (Manna, Bhuyan, and Ghosh 2018) Also is a potent Voltage-Gated Calcium Channel (VGCC) antagonist derivative which acts as an anti-hypertensive, anti- anginal, anti-tumor, anti-inflammatory, anti-tubercular, anti-cancer, anti-hyperplasia, anti-mutagenic, anti-dyslipidemic, and anti-ulcer agent (Mishra, Bajpai, and Rai 2019).

Abbreviations: FFMI - Fat-Free Mass Index, BP - Blood pressure.

^∗ CAS number.

SIRT1 expression increases in response to hunger or food restriction. During short-term famine, the cyclic AMP-activated factor (CREB) migrates through glucagon into the cell nucleus, binds to the promoter of the SIRT1 gene, and induces its expression. Simultaneously, high protein kinase A activity inhibits the translocation of the transcription factor that binds the carbohydrate response sequence (ChREBP) from the cytoplasm to the nucleus, thereby reversing its inhibitory effect on SIRT1 expression.

This process occurs during starvation for more than 24 h and is likely associated with deacetylation, and consequently, the inactivation of CREBP by SIRT1. When food is available, the glucose level in the cells increases, leading to rapid activation of ChREBP in the nucleus, where it suppresses the expression of the SIRT1 gene (Noriega et al. 2011).

In another study, a low-calorie diet was preferable to the Sirtuin-1 activator resveratrol. In patients with nonalcoholic fatty liver disease, the calorie-based diet reduced weight, BMI, waist circumference, waist-to-hip ratio, alanine aminotransferase, aspartate aminotransferase, and lipid profiles compared to resveratrol with placebo (Asghari et al. 2018).

Effect of nutrients on inhibition of SIRT1 expression

An excessive supply of energy leads to inhibition of the expression and activity of sirtuins. A high-fat diet (HFD) has been shown to reduce hepatic function (Valdecantos et al. 2012, 2017), and skeletal muscle (Haohao et al. 2015) expression of SIRT1 and SIRT3. This may be related to studies in which short or long-term HFDs and high ethanol consumption synergistically induce acute liver injury in mice (Chang et al. 2015).

The long-term use of a high-carbohydrate diet reduces SIRT1 expression more than an HFD with the same energy value. A high intake of carbohydrates in the diet, without excessive energy, leads to fatty liver and inhibition of NAMPT activity. Decreased SIRT1 levels under a high-carbohydrate diet are associated with increased miR-34 expression, which directly inhibits NAMPT in obesity (Li et al. 2015).

High levels of simple sugars in the body inhibit sirtuin activity. In vitro studies on tubular endothelial cells have shown that glucose inhibited SIRT1 expression (Zhou et al. 2015). In in vivo studies, a decrease in all SIRT1-SIRT7 sirtuins was observed in the hearts of mice with type 1 diabetes. Animals with type 2 diabetes have lower SIRT1 and SIRT2 levels and increased SIRT3 levels in the heart muscle (Bagul, Dinda, and Banerjee 2015).

Excess fructose may also contribute to a disturbance of sirtuin expression. The muscles of mice fed a fructose-rich diet exhibited increased levels of advanced glycation products (AGE), which inhibited the activation of SREBP-1c, thereby increasing the intensity of hepatic lipogenesis. The decrease in SIRT1 activity induced by AGE was also associated with a change in muscle fiber composition and a decrease in muscle strength. These studies indicate the possible negative effects of excessive dietary fructose on the risk of malnutrition (Mastrocola et al. 2016).

Effect of nutrients on the induction of SIRT1 expression

Adequate dietary intake of branched-chain amino acids is important for regulating sirtuin activity. Higher SIRT1 expression in the heart and diaphragm was observed in mice fed 1.5 mg branched-chain amino acids/kg/day compared to animals without supplementation. Additionally, physical activity amplifies this effect. Leucine increased the expression of SIRT1 in the liver, brown fat, and skeletal muscle of mice fed high-fat and low-fat diets (Li et al. 2012).

Studies have shown that certain substances can induce SIRT1 activity. Bogacka et al. showed that in non-diabetics, SIRT1 levels in adipose tissue were increased when caffeine, ephedrine, and the oral antidiabetic drug pioglitazone were administered concomitantly (Bogacka et al. 2007).

The intake of bioactive lipids in the diet appears to have a positive effect. Studies have shown that polyunsaturated fatty acids stimulate SIRT1 by kinase A-dependent activation of the SIRT1-PGC1α complex, thereby increasing the oxidation rate of fatty acids and preventing aging-related lipid dysregulation (Das 2021).

Other studies have shown that components of dairy products can act as SIRT1 activators. The consumption of dairy products leads to systemic changes that can promote the biogenesis of mitochondria in important target tissues, such as muscle and fatty tissue, both by direct activation of SIRT1 and by SIRT1-independent pathways (Bruckbauer and Zemel 2011). Leucine administration stimulates mitochondrial biogenesis and fat metabolism in both adipocytes and muscle cells. These effects were partly mediated by SIRT1 and were significantly attenuated by SIRT1 (Sun and Zemel 2009).

Materials and methods

Search strategy

PubMed databases were used to identify studies with the combined search terms such as sirt 1 AND inflammation, sirt 1 AND malnutrition, sirt 1 AND undernutrition, and with single search terms such as malnutrition, undernutrition, elderly, sirtuin 1, inflammation, oxidative stress, sarcopenia, frailty, weakness syndrome, biomarkers of inflammation, biomarkers of undernutrition, biomarkers of malnutrition, caloric restriction, aging, and nutritional status. In order to increase the accuracy of the literature search on the subject of the work, the year of publication was not definitively limited. The inclusion criteria were publications in English, such as randomized controlled trials, clinical trials, meta-analyses, and systematic reviews. Publications involving animal experiments were also included. To better identify relevant studies and journals, review and original articles were searched manually using the ISNN journal databases. The search terms are shown in Figure 1. Duplicates and publications based only on abstracts were excluded (Figure 2).

Figure 1. Shows the exact search terms used.

Figure 2. Flowchart of literature selection.

Effects of malnutrition on SIRT1 activity

Reduction of body reserves after level 1—insufficient nutrient intake, including metabolic disorders, increased demand, undernourishment, or excessive weight loss leads to depletion of body reserves and mild undernourishment (step 2). Minor signs of malnutrition lead to simple, uncomplicated dietary hunger (Level 3). During prolonged fasting, hunger, or extreme diets, NAD + levels increase as both NAD + biosynthesis and oxidation to NAD + increase (Cantó, Menzies, and Auwerx 2015). This leads to an increase in SIRT1 as a result of NAD + expression (step 3). The last stage of the pathomechanism of malnutrition is the occurrence of organ lesions and adverse changes in the body, such as increased catabolism and reduced protein, fat, and energy requirements within 24 h, which contribute to a decrease in SIRT1 levels in the body. According to previous studies, SIRT1 decreases in the fasting state of the pancreas, and during this time the mitochondrial uncoupling protein 2 increases, which may explain the lower insulin secretion due to calorie reduction (Bordone et al. 2006). A decline in SIRT1 is caused by long-term starvation, which leads to a physiological reduction in insulin and fasting glucose levels. A decrease in SITR1 in the pancreas may also be associated with malnutrition, as described in the three types of inflammatory disease-related malnutrition (DRM), non-inflammatory DRM, and disease-free malnutrition (Cederholm et al. 2017). However, the exact role of fasting in the activity of SIRT1 is not yet fully understood and appears to vary from tissue to tissue (Chen et al. 2008).

The pathomechanisms of malnutrition and possible SIRT1 relationship are shown in Figure 3 (in-house development based on the ESPEN guidelines).

Figure 3. The pathomechanism of malnutrition and the effects of malnutrition on blood SIRT1 levels. Inadequate supply of food constituents contributes to the depletion of body reserves, which in turn leads to disruptions of physiological processes and disruptions of biochemical processes. These changes lead to minor symptoms of malnutrition, which lead to starvation of the uncomplicated simple depending on the diet. The uncomplicated simple hunger increases the expression of NAD⁺, which in turn increases the expression of SIRT1. However, the persistent depletion of the body’s reserves leads to more severe organ damage, which manifests itself in catabolism, protein loss in the body, fat loss, energy demand and glycogen loss in the body within 24 h. This leads to a decrease in the level of SIRT1 in the body. Unfavorable organ changes contribute to malnutrition, which can affect DRM + I, DRM − I, Malnutrition without disease, depending on the severity (DRM disease related malnutrition—ESPEN). Authors own study based on Bordone et al. (2006); Cantó, Menzies, and Auwerx (2015); Cederholm et al. (2017); Chen et al. (2008); McClain, Kirpich, and Smart (2017); Nemoto, Fergusson, and Finkel (2004).

SIRT1 is involved in glycolipid metabolism in the liver. In short-term hunger, SIRT1 may inhibit target of rapamycin C2, which in turn inhibits gluconeogenesis and lowers blood sugar levels. Short-term fasting increases the expression and concentration of SIRT1 (Nemoto, Fergusson, and Finkel 2004). During prolonged starvation, SIRT1 deacetylates and activates the substrates peroxisome proliferator-activated receptor alpha (PPARα) and PPAR-γ co-activator-1α (PGC-1α), which contribute to the oxidation of fatty acids and improvement of glucose homeostasis. Second, SIRT1 deacetylates forkhead box 01 (FOX01) and signal transducers and activators of transcription 3 (STAT3) by promoting gluconeogenesis and inhibiting glycolysis, respectively. SIRT1 deacetylates FOX01 in hepatocytes, thereby releasing glucose. Long-term starvation contributes to a reduction in SIRT1 levels. The dietary status in liver disease may depend on factors such as overeating, malnutrition, or altered metabolism (McClain, Kirpich, and Smart 2017). Patients with complications such as liver disease, ascites, and hepatic encephalopathy have been shown to have a higher incidence of sarcopenia and malnutrition (Knudsen et al. 2016). The role of SIRT1 in hepatic glycolipid metabolism appears to be promising, and activation of SIRT1 may be beneficial not only in metabolic disorders and aging retardation, but also in malnutrition (Bonda et al. 2011; Mouchiroud et al. 2013). The fasting hepatic glycolipid metabolism by sirtuin 1 is shown in Figure 4.

Figure 4. Effect of SIRT1 in hepatic glycolipid metabolism under starvation. Authors’ own study based on Hallows, Yu, and Denu (2012); Horton, Goldstein, and Brown (2002); Purushotham et al. (2009).

The human defense system consists of different enzymatic and non-enzymatic components (Harman 1956). These enzymes include glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd), superoxide dismutase (SOD), and catalase. Non-enzymatic substances include endogenous antioxidants, such as reduced glutathione (GSH), ubiquinone (coenzyme Q10), uric acid, alpha lipoic acid, metallothionein, albumin, transferrin, and ceruloplasmin, as well as exogenous antioxidants, such as vitamin E (especially a-tocopherol), carotenoids (β-carotene, α-carotene, lycopene, lutein, zeaxanthin, astaxanthin, and canthaxanthin), vitamin C, flavonoids, mannitol, aminoguanidine and pyridoxine (Ferreira et al. 2011; Vasconcelos et al. 2007).

Elderly people with poor nutrition and malnutrition have low body weight, which in turn predisposes them to a variety of complications, such as reduced immunity (Lesourd and Mazari 1997), functional impairment (Moreira 2011), frailty (Wu et al. 2009) (with involuntary weight loss, fatigue, weakness, reduced walking speed, and physical activity) (Macedo, Gazzola, and Najas 2008), and an increase in morbidity and mortality (Vetta et al. 1999).

Chronic malnutrition has been shown to increase oxidative stress as albumin concentration in the body decreases, which in turn can act as an antioxidant (Fechner et al. 2001). Malnutrition followed by hypoalbuminemia increases oxidative stress in the plasma and liver (Fechner et al. 2001; Manary, Leeuwenburgh, and Heinecke 2000; van Zutphen et al. 2016).

Excessive oxidative stress impairs mitochondrial function due to mitochondrial DNA failure (Nissanka and Moraes 2018). Malnutrition may increase oxidative stress in skeletal muscles, which are rich in mitochondria. It has been shown that cellular oxidation can occur during the aging process itself and that these factors carry the risk of chronic diseases in older people (Halliwell and Gutteridge 2015). Oxidative stress causes cell aging, increasing the role of SIRT1 in protecting cells from aging by regulating FOX0, p53, and p21, as well as molecules involved in DNA damage and repair (Furukawa et al. 2007; Yao and Rahman 2012).

There is an association between plasma levels of oxidative stress markers (8-iso-PGF2α and 8-oxo-dGuo), nutritional status indicators (BMI), and cardiovascular risk (waist-hip ratio) (Tôrres et al. 2013).

Studies show that SIRT1 regulates oxidative stress and cellular toxicity (Chua et al. 2005; Kitamura et al. 2005). Causes may include SIRT1-mediated induction of manganese peroxide dismutase (MnSOD) by deacetylation and activation of the transcription factor FOX03. Research shows that the induction enhancer is resveratrol, which increases resistance to oxidative stress in myoblasts (Tanno et al. 2010). In other studies, FOX03 activation has also been shown to protect against oxidative stress caused by MnSOD (Kops et al. 2002; Li et al. 2006). SIRT1 expression and FOX03 deacetylation, which results in increased catalase expression, also protects the heart from oxidative stress in mouse models (Alcendor et al. 2007). Liver SIRT1 deficiency increases ROS production, impairing TOR/Akt signaling in other insulin-sensitive organs, resulting in insulin resistance (Kume et al. 2006).

SIRT1 inhibits IKB kinase, which in turn inhibits IKB degradation and, thus, the inflammatory response. Activation of SIRT1 leads to deacetylation and activation of the transcription factor FOX03, resulting in the production of catalase and MnSOD. Both compounds reduce oxidative stress. The mechanism for regulating oxidative stress and inflammation by SIRT1 is shown in Figure 5.

Figure 5. SIRT1 regulations in oxidative stress and inflammatory responses.

These studies suggest that oxidative stress, inflammation, and malnutrition are closely associated (Hirabayashi et al. 2021). Inflammation associated with disease is often observed in undernourished individuals. Inflammation affects the body’s need for nutrients as well as food intake, including appetite. It contributes to changes in metabolism, including increased resting energy consumption and increased muscle catabolism (Jensen 2015). Furthermore, malnutrition impairs the metabolic capacity of both fast and free muscles owing to AMP-activated protein kinase (AMPK)-independent inhibition of SIRT1 through increased oxidative stress (Hirabayashi et al. 2021).

Long-term moderate calorie restriction without undernutrition induces significant and sustained inhibition of inflammation without worsening key indicators of cellular immunity in vivo (Meydani et al. 2016).

Oxidative stress contributes to inflammation and malnutrition. Malnutrition can manifest as inflammation and increased oxidative stress; together, all these factors may lead to a decrease in SIRT1 expression. Decreased SIRT1 expression is associated with inflammation, oxidative stress, and malnutrition and is associated with the acetylation of NF-κB, an important redox-sensitive transcription factor responsible for the transcription of pro-inflammatory genes (Toledano and Leonard 1991). Inflammatory cytokines, such as interleukin-8 (IL-8), IL-6, and TNF-α are involved in the activation of immune cells and an inflammatory reaction. One of the main sources of these pro-inflammatory mediators are macrophages at the site of injury. In these cells, the transcription of these cytokines is regulated by NF-κB which undergoes various post-translational modifications, including phosphorylation and acetylation (Chen et al. 2005). Acetylation, together with phosphorylation, plays an important role in regulating the nuclear activity of NF-κB. Both p300 and CBP transferases have been reported to acetylate the RelA/p65 subunit NF-αB at Lys218, Lys221, and Lys310 (Chen, Mu, and Greene 2002). Acetylation of separate lysine residues in RelA/p65 modulates various functions of NF-κB, including transcription activation, DNA binding, and folding with its Iα inhibitor (Lanzillotta et al. 2010). After reduced NADH+, SIRT1 is degraded with simultaneous acetylation of NFKB and ReIA/p65 and the release of inflammatory mediators, which in turn may lead to malnutrition associated with inflammation and oxidative stress. The relationship between the factors that may stimulate reduced SIRT1 expression is shown in Figure 6.

Figure 6. Possible factors that stimulate a decrease in SIRT1 expression in the body Degradation of SIRT1 by NAD + waste with simultaneous acetylation of NF-KB and ReIA/p65 and release of inflammatory mediators. Authors’ own study based on literature Abdelmohsen et al. (2007).

SIRT1 in frailty

Kumar et al. revealed that blood sirtuin levels are associated with geriatric fragility syndrome (Kumar et al. 2014). SIRT1, SIRT2, and SIRT3 were significantly lower in subjects with frailty syndrome than in those without, persisting after correction for independent factors such as number of concomitant diseases, sex, age, cognitive impairment, diabetes mellitus, and hypertension. In another study, circulating SIRT1 was higher in weak older adults, including those with weight loss (Ma et al. 2019).

While the evaluation of inflammatory biomarkers is useful in assessing the risk of undernutrition in relation to severe diseases in which they play a role, the association of SIRT1 with frailty is quite promising, as it may indicate significant sensitivity and specificity, without an ongoing inflammatory process in malnutrition.

SIRT1 as potential malnutrition biomarker

Many studies point to an association between DRM and inflammation, oxidative stress, and organ dysfunction, including endothelial dysfunction in patients with inflammatory DRM (Bañuls et al. 2019; Solmi et al. 2015; Victor et al. 2009). The role of oxidative stress regulation of SIRT1 in the potential inflammatory mechanism and aging has been described in the literature (Hwang et al. 2013), but the role of SIRT1 as a biomarker for malnutrition has not yet been described.

While calorie restriction without malnutrition promotes longevity and delays aging in the SIRT1 regulatory mechanism (Fontana, Partridge, and Longo 2010), the effects of prolonged calorie restriction and hunger on the severity of undernourishment are not well described.

In one study, SIRT1 levels were measured in three age groups (children, adults, and the elderly) to understand how SIRT1 levels change with age. The relationship between the polymorphisms of the single nucleotide SIRT1 (rs7 895 833 A > G in the promoter region, rs7 069 102 C > G in intron 4, and rs2 273 773 C > T in Exon 5—silent mutation) and the expression levels of SIRT1, endothelial nitric oxide synthase, and paraoxonase-1 were investigated. Paraoxonase 1 (PON-1), cholesterol levels, total antioxidant status (TAS), total oxidation status, and oxidation stress index (OSI) increased with increasing age in a Turkish population. A significant increase in SIRT1 levels was observed in elderly patients and a significant positive correlation between SIRT1 levels and age was observed in the overall study population. The oldest individuals with the AG genotype for rs7 895 833 had the highest SIRT1 value, suggesting a relationship between rs7 895 833 SNP and longevity. Elderly patients had a higher OSI and lower PON-1 levels than adults and children, which may lead to high SIRT1 levels as a compensatory mechanism for oxidative stress in the elderly. In addition, a decrease in low-density lipoprotein (LDL) levels has been observed in elderly patients and a positive correlation between high-density lipoprotein (HDL) cholesterol and SIRT1 levels has been observed in elderly patients (Kilic et al. 2015). The aging process itself contributes to the oxidative damage of DNA, which in turn leads to an increase in ROS, a higher rate of oxidative stress, and is an important factor in the occurrence of age-related diseases (Bohr 2002). Oxidative stress induces a reduction in NAD + by activation of PPAR, which in turn results in reduced expression of SIRT1. In vivo studies in rats have shown that this mechanism plays an important role in aging. In other studies, TAS was higher in elderly patients than in adults, but did not differ significantly from TAS levels in children. This may be related to the high SIRT1 levels in older people and the role of SIRT1 in the induction of antioxidants (Olmos et al. 2013).

Many studies have shown that the oxidative stress caused by TAS and total, LDL, and HDL cholesterol is associated with SIRT1 levels in the elderly. The correlation between cholesterol and SIRT1 levels may be explained by changes in hepatic metabolism associated not only with age, but also with malnutrition associated with metabolic disorders (Morena et al. 2000). Older people have lower HDL cholesterol and higher LDL cholesterol levels than younger people. Some studies have shown that higher LDL-C levels in elderly patients are associated with increased mortality mainly due to oxidative stress and inflammatory reactions (Benn, Tybjærg-Hansen, and Nordestgaard 2019; Yeboah 2018).

A Chinese study found an association between the LDL-C/HDL-C ratio and overall mortality in elderly patients with hypertension. Both low and high LDL-C/HDL-C ratios resulted in higher overall mortality, and patients with an LDL-C/HDL-C 1.67–2.10 had a significantly higher chance of survival (Yu et al. 2020).

El Assar et al. have shown that the improvement in nutritional status, as measured by MNA in older people, regardless of frailty syndrome or adherence to the Mediterranean diet, is positively associated with SIRT1 gene expression. The increased risk of malnutrition (based on MNA scores) was significantly associated with lower SIRT1 expression, confirming that older people with good nutrition have higher SIRT1 expression levels. These findings suggest that Sirtuin 1 is a potential biomarker for health interventions in the elderly (El Assar et al. 2018).

This work underlines the importance of sirtuins in the context of malnutrition in older people. Malnutrition, with or without inflammation or DRM caused by calorie restriction, may be associated with changes in SIRT1 expression in the cell nucleus. Calorie reduction has been shown to have a positive effect on longevity and aging and calorie restriction alone should not be equated with malnutrition (Michan 2014).

However, it should be noted that sirtuin activity is influenced by nutrient availability. SIRT1 levels increase during fasting or calorie reduction with negative energy balance (Rodgers and Puigserver 2007). Nutrient values (e.g., glucose, lipids, and amino acids) were measured with AMPK, SIRT1, or mTOR energy sensors (Escobar et al. 2019; Finkel 2015; Nemoto, Fergusson, and Finkel 2004). Malnutrition without disease may be associated with a short-term calorie reduction, which in turn activates AMPK or SIRT1 but inhibits mammalian target of rapamycin (mTOR), which is reduced in nutrient deficiency. Long-term calorie restriction and malnutrition with or without inflammation, decreases NADH+, which reduces the expression of SIRT1. Simultaneous deacetylation of STAT3 and FOX01 in hepatocytes, results in the transfer of SIRT1 from the nucleus to the cytosol and degradation of SIRT1. Figure 7 shows SIRT1 as a potential biomarker of nutritional status in the mechanism of decreasing and increasing activity in the cell nucleus.

Figure 7. SIRT1 as potential malnutrition biomarker (nucleus). Authors’ own study.

Conclusions

The key to successful treatment of the elderly is early detection of undernutrition and its risk factors, and the earliest possible application of therapy. Animal studies point to potential molecular mechanisms regulating sirtuin 1 expression. In this review, we proposed the pathomechanism and pathway of sirtuin 1 activation and attempted to explain how malnutrition affects sirtuin 1 expression. Studies suggest that short-term fasting can increase SIRT1 expression, while long-term fasting can have the opposite effect. Some studies suggest a potential link between sirtuin 1 and nutritional status in older adults. However, these data, with the current state of knowledge are limited to a small number of human and animal studies, and therefore require further research to confirm the potential of sirtuin 1 as a biomarker of age-related undernutrition. When evaluating the usefulness of sirtuin 1 as a biomarker of undernutrition in humans, it is important to consider other medical conditions that may themselves cause changes in sirtuin 1 concentration and, on the other hand, chronic diseases may lead to malnutrition. Taking all these factors into account, further studies are desirable to confirm the role of sirtuin 1 in malnutrition and to investigate the predictive value, specificity and sensitivity of sirtuin 1 as a biomarker.

Author contributions

Writing–original draft preparation, K.K.; writing—review and editing, K.K. and A.W.

Availability of data and material

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations
AGE	=	Advanced glycation products
AMPK	=	AMP-activated protein kinase
BMI	=	Body Mass Index
ChREBP	=	Carbohydrate response sequence
CREB	=	AMP-activated factor
DRM	=	Disease-related malnutrition
FFA	=	Free fatty acids
FOX0	=	Forkhead box 0
FOX01	=	Forkhead box 01
FOX03	=	Forkhead box 03
GSH	=	Reduced glutathione
GSH-Px	=	Glutathione peroxidase
GSH-Rd	=	Glutathione reductase
HDACs	=	Histone deacetylases
HDL	=	High-density lipoprotein
HFD	=	High-fat diet
IL1	=	Interleukin-1
IL6	=	Interleukin-6
IL-8	=	Interleukin-8
LDL	=	Low-density lipoprotein
mTOR	=	Mammalian target of rapamycin
MNA	=	Mini-Nutritional Assessment
MnSOD	=	Manganese peroxide dismutase
MUST	=	Malnutrition Universal Screening Tool
NAD	=	Histone-nicotinamide adenine dinucleotide
NAMPT	=	Nicotinamide phosphoribosyltransferase
NF-αB	=	Nuclear factor αB
NRS-2002	=	Nutrition Risk Screening
OSI	=	Oxidation stress index
PGC-1α	=	Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
PON-1	=	Paraoxonase 1
PPARα	=	Peroxisome proliferator-activated receptor alpha
ROS	=	Reactive oxygen species
SIR2	=	Silent information regulator 2
SIRT1	=	Sirtuin 1
SOD	=	Superoxide dismutase
SGA	=	Subjective Global Assessment Short Form
STAT3	=	Signal transducers and activators of transcription 3
TAS	=	Total antioxidant status
TNFα	=	Tumor necrosis factor-alpha

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was not supported.