Serine metabolism in aging and age-related diseases

Abstract

Non-essential amino acids are often overlooked in biomedical research; however, they are crucial components of organismal metabolism. One such metabolite that is integral to physiological function is serine. Serine acts as a pivotal link connecting glycolysis with one-carbon and lipid metabolism, as well as with pyruvate and glutathione syntheses. Interestingly, increasing evidence suggests that serine metabolism may impact the aging process, and supplementation with serine may confer benefits in safeguarding against aging and age-related disorders. This review synthesizes recent insights into the regulation of serine metabolism during aging and its potential to promote healthy lifespan and mitigate a spectrum of age-related diseases.

Introduction

Serine is classified as a nutritionally nonessential amino acid (NEAA); however, metabolically, serine plays critical roles in central metabolism. It is involved in the synthesis of essential biomolecules, including proteins, sphingosine, lipids, and nucleotides [1–3], and it affects numerous aspects of animal physiology. Its metabolic products are important for cell proliferation, tissue development, and specific organ functions. For example, serine is converted into intermediates used in glycolysis for energy production, and its catabolic products are essential for one-carbon metabolism, involving folate and methionine [2]. As a key one-carbon donor to the folate cycle, serine is also important to nucleotide synthesis, methylation reactions, and the generation of NADPH for antioxidant defense [4]. Therefore, serine is a metabolically essential amino acid, playing a significant role in a wide range of biological functions [5].

As an NEAA, serine can be derived exogenously in the diet and endogenously through the de novo serine synthesis pathway (SSP) [6, 7]. Increased serine can enhance intestinal immune and antioxidant functions [8, 9], regulate intestinal flora both in vitro and in vivo [10], and promote growth and development [11, 12]. Under oxidative stress or bacterial infection conditions, endogenous serine is often insufficient to meet cellular demands, thus necessitating exogenous serine supplementation to alleviate stress responses [10, 13]. In addition, aberrant metabolic fluxes associated with serine metabolism have emerged as potential risk factors for various age-related diseases (ARDs) and their comorbidities. For instance, impaired endogenous serine synthesis is associated with the development of ARDs, including Alzheimer’s disease [14], cardiovascular disease [15], diabetes [16], and fatty liver disease [17], and increasing evidence suggests that targeting serine metabolism may provide novel potential therapeutics to improve aging associated negative health outcomes, as demonstrated in various animal models [18–20].

Here, we review recent advances in the regulation of serine metabolism in the aging process, highlighting serine’s potential pro-longevity role and therapeutic promise for numerous age-related disorders. We first provide a comprehensive guide for researchers interested in understanding serine metabolism and its downstream metabolites. Then, we focus on the impact of serine on a wide range of biological functions in the aging process.

Serine sources

1. Serine biosynthesis from glucose

The serine synthesis pathway (SSP) utilizes glucose via diversion of the glycolytic intermediate 3-phosphoglycerate (3PG) to synthesize serine through a series of three enzymatic steps (Fig. 1). In the first step, 3PG is converted to 3-phosphohydroxypyruvate (3PHP) by phosphoglycerate dehydrogenase (PHGDH). Next, phosphoserine aminotransferase 1 (PSAT1) catalyzes 3PHP into 3-phosphoserine (3PSer). Lastly, phosphoserine phosphatase (PSPH) converts 3PSer into serine [4]. De novo serine biosynthesis from glucose is highly active in a wide variety of cell types such as astrocytes [14], macrophages [21], and epidermal stem cells [22], as well as specific organs including the central nervous system (CNS) [23], liver [24], and the kidney [25].

• 2.Serine regeneration from glycine

Fig. 1.

Major sources, metabolites, and biosynthetic pathways for serine. Colors indicate if a metabolite has been shown to have pro-longevity (red) or longevity shortening (blue) effects. Metabolites lacking a color have unknown or conflicting effects on longevity. Figure produced in BioRender

L-serine can be synthesized de novo from glycine, a closely related NEAA. Serine hydroxymethyltransferase (SHMT) catalyzes the reversible conversion of glycine to serine. SHMT transfers a one-carbon unit from 5,10-methylene-tetrahydrofolate (5,10-MTHF) to glycine, producing tetrahydrofolate (THF) and L-serine [26, 27]. L-serine and glycine are rapidly converted in reactions catalyzed by two protein isoforms of SHMT located in the cytosol (SHMT1) and mitochondria (SHMT2) [28, 29]. In healthy humans, the synthesis of L-serine by SHMT constitutes approximately 41% of the total glycine flux throughout the body [30].

• 3.Serine uptake and transport from the diet

The primary dietary source of L-serine is protein, with 2 to 5% of the amino acid content of plant-based and animal-based proteins being L-serine [31]. Lipids, which contain serine in the form of phosphatidylserine and sphingolipids, contribute minimally to dietary serine intake. This is due to the low phosphatidylserine content in the diet, and most sphingolipids are either used by the intestinal mucosa or excreted in feces [32]. Therefore, the average daily intake of serine from food sources for an adult is estimated to be approximately 3.5 g [33–35].

• 4.Serine recycled from protein breakdown

Serine can also be produced through the degradation of serine-containing proteins in the lysosome, a process that breaks down deactivated or misfolded endogenous proteins during autophagy [36]. Assuming that the serine content in human muscle protein is approximately 2.3% [31] and recognizing the significant role of skeletal muscle in protein turnover, which is about 300 g per day in a 70 kg individual, it is estimated that approximately 6.9 g (65.1 mmol) per day of L-serine is released during the degradation of endogenous proteins. This estimation aligns closely with measurements of the rate of serine appearance following an overnight fast (~ 58 mmol per day) using stable isotope tracers [37].

Major metabolites of serine and their related physiological importance

In addition to serine itself, serine metabolism also produces multiple metabolites crucial for human health, which we describe in this section. Serine racemase (SR) catalyzes the conversion of L-serine to D-serine, which acts as a neuromodulator by binding to and activating the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors [38].

As stated above, L-serine can be converted to glycine in both the cytosol (SHMT1) and mitochondria (SHMT2) [28, 29]. Glycine, a precursor for multiple metabolites including glutathione, porphyrins, purines, heme, and creatine, plays a significant physiological role in both humans and animals. It functions as a neurotransmitter in the CNS and exhibits various roles in peripheral and nervous tissues, such as acting as an antioxidant, anti-inflammatory agent, cryoprotectant, and immunomodulator [39].

L-serine is degraded to pyruvate via serine dehydratase (SDH) [40]. Pyruvate serves as a fuel input for the citric acid cycle (also known as the Krebs cycle or TCA cycle). These reactions produce ATP as well as intermediates essential for various major biosynthetic pathways including gluconeogenesis, nucleotide, and lipid synthesis [41]. Additionally, pyruvate acts as a protective antioxidant in the brain and other tissues susceptible to oxidative stress [42, 43].

Serine also contributes to the production of nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and S-adenosylmethionine (SAM) through participating in one-carbon metabolism, which includes the folate and methionine cycles [44]. NADPH, a coenzyme acting as an electron transporter, supports various anabolic processes and has strong antioxidant properties that help maintain cell growth [45]. GSH is ubiquitously present in all mammalian tissues as the most abundant non-protein thiol, preventing damage due to oxidative stress [46]. Additionally, GSH is essential for the detoxification of xenobiotics, and it regulates cell proliferation, apoptosis, immune function, and fibrogenesis [47]. SAM functions as the principal biological methyl donor for histone and DNA methylation processes [48]. SAM is converted into S-adenosyl-L-homocysteine (SAH), which in the liver, serves as a precursor for GSH through conversion into cysteine via the trans-sulfuration pathway [49]. Additionally, SAH donates an aminopropyl group for spermidine synthesis [50]. Spermidine, a natural polyamine, induces cytoprotective autophagy, facilitating the turnover of cytoplasmic organelles and long-lived proteins.

Serine can also lead to the production of ceramide lipids. A ceramide consists of sphingosine and a fatty acid linked by an amide bond. Ceramide acts as the backbone of sphingolipids such as sphingomyelin (SM), cerebrosides, and gangliosides and is therefore an important component of the plasma membrane in eukaryotic cells [51, 52]. As a bioactive lipid, ceramide is involved in numerous functions, including apoptosis, cell growth arrest, differentiation, cell senescence, cell migration, and cell adhesion [53]. SM is found in animal cell membranes, particularly in the myelin sheath that encases some nerve cell axons and in plasma lipoproteins [54]. SM plays a critical role in cellular signaling by serving as a reservoir for lipid signaling molecules and facilitating the formation of SM-enriched membrane domains. These domains regulate the clustering of signaling molecules, thereby promoting efficient signal transduction [55].

In addition to serine’s direct downstream metabolites, the serine biosynthesis pathway is crucial for generating alpha-ketoglutarate (α-KG), a key intermediate in the tricarboxylic acid (TCA) cycle. PSAT1 utilizes 3PHP, produced by PHGDH (Fig. 1), to facilitate the transamination of glutamate to produce α-KG [56, 57]. α-KG is integral to various metabolic processes, including amino acid synthesis, nucleotide production, and cellular energy generation [58, 59]. Beyond its metabolic role, α-KG is essential for maintaining mitochondrial homeostasis [60, 61], supporting antioxidative defenses [62], reducing inflammation [63], promoting cell proliferation [64], and even exerting tumor-suppressive effects [65]. These diverse functions underscore α-KG’s importance not only in energy metabolism but also in broader cellular homeostasis and defense mechanisms.

Serine metabolism in aging and aging-related diseases

Aging is characterized by a progressive decline of physiological integrity, leading to impaired function, heightened susceptibility to chronic diseases, and increased mortality risk [66]. This decline is often caused by and accompanied with overall nutrient deficiencies [67, 68], and nutritional interventions have potential to slow or reverse the aging processes across various organ systems, including the brain, cardiovascular system, gastrointestinal tract, skeletal structure, and skin [69]. Specifically, changes in amino acid metabolism have been increasingly recognized as key contributors to the aging process [70, 71]. While much of the research has traditionally focused on essential amino acids [72], recent studies have revealed that NEAAs, such as serine, may also play significant roles in late-life health and longevity. Understanding the complex relationship between serine metabolism and aging may potentially lead to the development of novel strategies to mitigate the adverse effects of aging and increase healthy lifespan. This section highlights the significant roles that serine metabolism plays in aging, longevity extension, and aging-related diseases, providing insights into potential therapeutic targets for longevity interventions, as well as denoting needed areas of future research.

Serine and aging and longevity

Recent studies on serine supplementation across various model organisms have revealed its potential role in extending lifespan. In C. elegans, supplementation with 10 mM serine has been shown to produce the greatest increase in lifespan—up to 22%—among the 20 proteogenic amino acids [73], indicating an important role of serine in lifespan extension. Moreover, serine supplementation alters mitochondrial TCA cycle metabolism and respiratory substrate utilization, contributing to the observed extended lifespan [74]. In yeast, L-serine supplementation extends chronological lifespan by mitigating acidification and working through the one-carbon metabolism pathway [75]. In addition, preclinical studies in rodents have also documented reductions in both circulating and hippocampal serine levels with age [76, 77].

In vitro studies utilizing human cells also underscore the importance of serine metabolism in the process of cellular senescence. Specifically, the inhibition of serine synthesis via CBR-5884, an inhibitor of phosphoglycerate dehydrogenase (PHGDH), in human primary Müller cells subjected to mild oxidative stress, results in a marked reduction in metabolic activity and a concomitant increase in cellular damage [78]. Corroborating these observations, overexpression of PHGDH in human vascular endothelial cells, which enhances de novo serine synthesis, effectively mitigates premature cellular senescence [79]. Similarly, in human dental pulp cells (DPCs), the inhibition of PHGDH-mediated serine biosynthesis triggers replicative senescence, highlighting the essential role of serine in sustaining cellular function and longevity [80]. Collectively, these preclinical studies demonstrate the potential involvement of serine metabolism in aging across diverse model organisms, as summarized in Table 1.

Table 1.

Preclinical studies for serine-relevant intervention increased lifespan

Study	Organism	Intervention	Effect on lifespan	Mechanism
Serine supplementation in C. elegans [74]	C. elegans	Serine supplementation	Extended lifespan	Altered mitochondrial TCA cycle metabolism and respiratory substrate utilization
Glycine/serine supplementation in C. elegans [73]	C. elegans	Glycine/serine supplementation	5 mM serine prolonged the lifespan of worms (+ 20.8% in median lifespan)	Serine-mediated longevity effect is dependent on the methionine cycle in a metr-1 and sams-1 dependent manner
Serine supplementation in yeast [81]	Budding yeast	Supplementation of serine in culture media	Extend the lifespan of budding yeast	Controls extracellular pH through catabolism into ammonium and acting as an energy source after glucose exhaustion
L-serine supplementation in C. elegans [82]	C. elegans	L-serine supplementation	5 mM serine can increase the lifespan of wild type worms	De novo serine biosynthesis is required for longevity upon mitochondrial protein import system suppression (MitoMISS)
L-serine supplementation in budding yeast [75]	Budding yeast	L-serine supplementation	Extend the chronological lifespan of yeast	Supplementing L-serine into NR cultures extended chronological life span through a mechanism dependent on the one-carbon metabolism pathway
Inhibition de novo serine synthesis in human cells [78]	Human primary Müller cells	Inhibition de novo serine synthesis using CBR-5884	Metabolic activities significantly reduced and cellular damage of Müller cells increased	De novo serine synthesis improved Müller cell survival by maintaining mitochondrial function and generating glutathione and NADPH to counteract ROS
Enhancement of de novo serine synthesis in human cells [79]	Human vascular endothelial cells	Overexpression of PHGDH in vascular endothelium (VE)	VE-specific overexpression of PHGDH prevents premature cellular senescence	L-serine attenuates senescence in endothelial cells by acting as a signal molecule to activate PKM2
Inhibition de novo serine synthesis in human cells [80]	Human dental pulp cells	Inhibition of PHGDH in human dental pulp cells	Inhibition of PHGDH leads to the phenotype of replicative senescence	PHGDH-mediated serine biosynthesis reduces H3K36me3 levels by providing less methylation donor SAM
Long-term L-serine administration in aging mice [83]	Age-related obesity with C57BL/6 J mice	L-serine were administered to old mice for 6 months	0.5% L-serine significantly reduced food intake and body weight gain	L-serine reduced body weight by decreasing orexigenic peptide expression and reduced oxidative stress and inflammation via Sirt1/NFκB pathway

In addition to its potential lifespan extending properties in animal models and cell culture, there is evidence that dietary serine consumption may also be associated with improved late-life health outcomes in humans. It has been well described that circulating serine levels decline with age in humans [84, 85], and lower plasma serine levels are associated with an increased risk of mortality in COVID-19 patients [86], as well as across different age groups [87]. The Ogimi village population, in the “blue zone” Okinawa [88], has exceptional lifespan that may be partly attributed to the high serine content in their diet [89]. The Ogimi diet features foods such as tofu and seaweeds, which are rich in L-serine. Notably, Ogimi women consume more than 8 g of L-serine per day, in stark contrast to the average intake of 2.5 g per day for women over 70 years old in the USA [89]. Given the apparent scarcity of progressive neurodegenerative illnesses among the Ogimi villagers, the substantial intake of L-serine potentially supports their neurological health and contributes to their exceptional longevity [89], though more prospective research is needed. These findings indicate that serine supplementation could potentially offer benefits for longevity, though most previous studies are observational in nature.

Serine and age-related diseases

Age is one of the greatest risk factors for numerous pathologies, such as neurodegenerative diseases [90, 91], type 2 diabetes [92], cardiovascular disease [93], and cancers [94]. All of these are often termed “age-related diseases” (ARDs), and aging and ARDs may share a common set of fundamental biological mechanisms [95, 96]. Interestingly, accumulating evidence indicates that serine deficiency is associated with various ARDs [14–17, 97, 98]; there are multiple human clinical trials as well as basic studies to investigate the therapeutic potential of serine in various ARDs, which we describe below, and animal studies are overviewed in Table 2.

Table 2.

Studies of serine improving aspects of age-related diseases in diverse animal models

Study	Animal models	Intervention	Effect on age-related pathologies	Mechanism
Maternal serine supplementation on high-fat diet-induced oxidative stress [99]	C57BL/6 J mouse dams during gestation with HF diet	1% serine supplementation during pregnancy	Maternal serine prevents oxidative stress and fat accumulation in weanlings from dams fed high-fat diet	Serine alleviates HF diet-induced oxidative stress by epigenetically regulating glutathione synthesis
L-serine supplementation in diquat-induced oxidative stress in mice [100]	Mice model of diquat-induced oxidative stress	L-serine was supplemented in the drinking water for 14 days	Serine supplementation improved glutathione synthesis and alleviated oxidative stress	Serine alleviated oxidative stress via supporting glutathione synthesis and methionine cycle
Effects of serine on acute pancreatitis during diabetes in mice [16]	Mouse model of diabetes	10% L-serine supplementation in diabetic mice	L-serine supplementation reduced the acinar tissue damage resulting from pancreatitis in diabetic mice	L-serine decreased the ROS production, ER stress and cellular apoptosis in acinar tissue
L‐serine in ALS/Parkinsonism dementia [101]	Rat model of ALS/Parkinsonism dementia complex	L-serine solution was injected intraperitoneally daily for 1 week into the model rats	Administration of L-serine enhanced cognitive function, and ameliorated electrophysiological abnormalities	L‐serine alleviated apoptotic and autophagic changes in the central nerve system
L-serine supplementation in autoimmune diabetes [102]	Autoimmune diabetic model in NOD mice	Supplementation of L-serine 85.7 g/L, or 280 mg/day/mouse in water	Supplementation of L-serine reduced diabetes incidence and insulitis score	L-serine protects against autoimmune diabetes by regulating pancreas sphingolipid composition
Long-term effects of L-serine supplementation in diabetic neuropathy [103]	db/db mice model for diabetic neuropathy	5–20% oral L-serine for 6 months	L-serine treatment significantly improved functional neuropathy and sensory modalities	L-serine suppresses neurotoxic deoxysphingolipids (1-deoxySLs) in db/db mice
Serine one-carbon metabolism in myocardial ventricular function [15]	Ventricular pressure overload murine model	Cardiac-specific overexpression of CnAβ1 in transgenic mice	Activation of serine and one-carbon metabolism in transgenic mice reduced cardiac hypertrophy and improved cardiac function	Activation of the serine and one-carbon pathway leads to the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production
Effects of L-serine in hypertensive rats [104]	Spontaneously hypertensive rats	L-serine (0.3–3.0 mmol/kg) was administered intravenously	L-serine evoked a greater maximal fall in mean arterial pressure	The antihypertensive effect of L-serine is likely mediated through the activation of endothelial KCa channels
Antihypertensive effect of L-serine [105]	NO synthase-inhibited hypertensive rats	Acute intravenous infusion of L-serine in rats	L-serine evoked a dose-dependent decrease in mean arterial pressure without increasing heart rate	L-serine promotes vasodilatation in resistance arterioles via activation of apamin and charybdotoxin/TRAM-34-sensitive K(Ca) channels present on the endothelium
The role of serine in nonalcoholic fatty liver disease [106]	Mouse model of HFD-induced hepatic lipid accumulation and injury	1% L-serine (wt/vol) was supplemented in drinking water for 8 weeks	Serine supplementation increased glucose tolerance and insulin sensitivity, and protected mice from hepatic lipid accumulation	Serine prevents HF diet-induced oxidative stress and steatosis by epigenetically modulating the expression of glutathione synthesis-related genes and through AMPK activation
Effects of L-serine on alcoholic fatty liver [107]	Ethanol-induced fatty liver model in mice and rat	Dietary 1% L-serine supplementation for 2 weeks	L-serine decreased hepatic neutral lipid accumulation and increased glutathione and S-adenosylmethionine	L-serine ameliorated alcoholic fatty liver by accelerating L-serine–dependent homocysteine metabolism
L-serine treatment in chronic liver injury [108]	CCl4-induced hepatic fibrosis mouse model	L-serine (100 g/L) treatment for 8 weeks	L-serine reduces inflammatory cell and collagen deposition and reduces hepatic fibrosis in the liver tissue	L-serine induces antioxidant production via the maintenance of NADPH production in the mitochondria
Effects of serine deficiency on hepatic fat accumulation in mice [5]	C57BL/6 J male mice	Mice fed a serine-deficient diet or PHGDH inhibitor NCT-503	Both treatments increased body and liver weight and triglyceride content in the liver, and exacerbated hepatic inflammatory responses and oxidative stress	Serine deficiency leads to hepatic fat accumulation by affecting the gut-microbiota-liver axis
Dietary serine in effector T cell expansion [109]	C57BL/6 and OT-I mice with infection	Animals were fed a test diet lacking serine for 2 weeks prior to infection	Restricting dietary serine impairs pathogen-driven expansion of T cells in vivo	Serine supplies glycine and one-carbon units for de novo nucleotide biosynthesis in proliferating T cells

Serine plays a pivotal role in neurological signaling to promote neuronal elongation, differentiation, and growth [110]. Additionally, L-serine serves as an essential neurotrophic factor and a precursor to neuroactive substances such as D-serine, glycine, and cysteine. These metabolic products are important for cell proliferation, neuronal development, and other functions within the mammalian CNS [111]. Recent research has highlighted the role of aberrant L-serine homeostasis as a potential modifier of Alzheimer’s disease (AD). For example, L-serine is reduced in brain tissue of AD patients as compared to normal controls [112], and a mouse model of AD exhibited decreased L-serine availability in the hippocampus, which was associated with synaptic deficits [14]. Treatment of AD patients with combined metabolic activators (CMA), where L-serine constituted 61.75% of the formulation, resulted in enhanced cognitive functions and improved clinical parameters [113]. L-serine has also been shown to protect against β-N-methylamino-L-alanine (L-BMAA)-induced neurotoxicity in both animal and cell culture models [114], and L-BMAA activates endoplasmic reticulum (ER) stress [115] and has been linked to neurodegenerative diseases [116, 117]. Cognitive decline, a common phenomenon among older adults, is often an early indicator of AD and related dementias [118, 119]. D-serine administration was shown to enhance cognitive function in older adults, suggesting a transfer of benefits to daily activities and overall health-related quality of life [120].

Moreover, studies deploying a mouse model of AD have shown that the de novo serine synthesis pathway (SSP) is disrupted in astrocytes [14]. In mice, the deletion of PHGDH, the first enzyme in the SSP, results in severe neurological defects and early postnatal death [121]. Furthermore, various serine-deficiency syndromes linked to mutations in the SSP have been identified in human patients, leading to neurological disorders that can be alleviated by substantially increasing dietary serine [122, 123]. Adeno-associated virus (AAV)-mediated inactivation of PHGDH in the brain led to reduced L-serine levels, impaired synaptic plasticity, and diminished spatial memory, demonstrating that reduced L-serine levels in the brain contribute to cognitive dysfunction [14]. Importantly, dietary L-serine supplementation in this model normalized L-serine and D-serine levels and improved spatial memory and cognitive function [14, 124]. These findings suggest that L-serine deficiency may contribute to the neuronal dysfunction associated with AD, and dietary L-serine supplementation may enhance cognitive function and mitigate the effects of AD.

In alignment with findings observed in AD, L-serine has also shown promising therapeutic effects in the treatment of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of cortical and lower motor neurons in the spinal cord and brainstem [125], leading to progressive muscle atrophy, fatigue, dysphagia, and eventually death [125, 126]. In a rat model of ALS/Parkinsonism dementia complex, administration of L-serine resulted in improvements in alleviating apoptotic and autophagic alterations, enhancing cognitive function, and ameliorating electrophysiological abnormalities [101]. Furthermore, in a clinical trial, ALS patients who received L-serine showed slowed ALS disease progression [127]. These findings suggest that L-serine may exert a neuroprotective effect in the treatment of ALS. Similarly, in hereditary sensory autonomic neuropathy type I (HSAN1), a slow progressive neurodegenerative disorder primarily affecting sensory nerves and often leading to severe disability, oral supplementation with high doses of L-serine was shown to significantly slow disease progression [128]. These studies suggest a therapeutic potential of L-serine as a general treatment for AD and other neurodegenerative diseases.

Serine supplementation may also hold therapeutic promise in addressing other age-related diseases and conditions. A notable association exists between advancing age and type 2 diabetes mellitus (T2DM) [129]. T2DM is primarily characterized by hyperglycemia, which arises from a progressive decline in insulin secretory capacity of β-cells, often coupled with varying degrees of insulin resistance [129]. Increasing evidence indicates that L-serine concentrations in both plasma and tissues are significantly diminished in individuals with T2DM [130–134]. In addition, a large study of 5181 non-diabetic men demonstrated that higher L-serine levels were associated with enhanced insulin secretion and sensitivity, thereby potentially reducing the risk of developing T2DM [135]. In an animal model of non-obese diabetes (NOD), supplementation with L-serine was shown to attenuate insulitis and decrease the incidence of diabetes compared to controls, which was linked to improved glucose tolerance, reduced insulin resistance, and a modest reduction in average blood glucose levels [102]. Additionally, in a murine model of streptozotocin (STZ)-induced diabetes, dietary L-serine supplementation reduced pancreatic acinar cell damage and lowered markers of pancreatitis, suggesting that L-serine may mitigate pancreatic injury [16]. Handzlik et al. [136] recently developed a novel model of serine-associated sensory neuropathy in diabetic mice, finding that serine depletion exacerbates lipid abnormalities and accelerates neurological decline. In addition, a serine-enriched diet reduced levels of neurotoxic 1-deoxysphingolipids in both liver and paw skin, while administration of myriocin, an SPT inhibitor, effectively decreased canonical sphingolipids in the liver. Both interventions alleviated sensory neuropathy progression, linking serine-associated neuropathy to sphingolipid metabolism and suggesting that targeting serine metabolism could be a promising therapeutic approach. The authors also introduced the “serine tolerance test” (STT), analogous to the oral glucose tolerance test, which holds the potential to identify patients at risk for sensory neuropathy due to serine dysregulation [136]. By linking insulin resistance, serine homeostasis, and lipid metabolism, the study underscores the therapeutic potential of serine-targeted interventions for diabetes-associated neuropathies. Furthermore, L-serine supplementation to mice fed a high-fat diet (HFD) enhanced glucose tolerance and insulin sensitivity [137]. Collectively, these findings indicate that L-serine supplementation may offer therapeutic benefits in the context of diabetes; however, future prospective studies are still needed.

Aging is also closely linked to the progression of chronic liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and alcoholic steatohepatitis [138], and dysregulation of serine metabolism may play a role in development and progression of these disorders. Notably, circulating serine levels are significantly reduced in patients with NAFLD [139], and serine deficiency has been implicated in the development of fatty liver disease [3]. Furthermore, animal models of HFD-induced steatosis and methionine-choline-deficient diet-induced steatohepatitis have reduced PHGDH expression [140], and overexpression of PHGDH in mice resulted in significantly reduced triglyceride accumulation in the liver, lower expression of lipogenic genes and proteins, and increased activity of SIRT1 [140, 141]. Interestingly, mice subjected to a serine-deficient diet or administered a PHGDH inhibitor exhibited increased body weight, liver weight, and triglyceride content in the liver [5]. Both interventions also exacerbated hepatic inflammatory responses and oxidative stress, suggesting that exogenous and endogenous serine deficiencies contribute to hepatic lipid accumulation and aggravate oxidative stress and inflammation in the liver [5]. Other potential therapeutic targets within the endogenous serine synthesis pathway, such as phosphoserine phosphatase (PSPH) and serine hydroxymethyltransferase 1 (SHMT1), have been identified for the treatment of NASH [3, 142]. In a mouse model of HFD-induced hepatic lipid accumulation and injury, L-serine supplementation improved glucose tolerance and insulin sensitivity and reduced hepatic lipid accumulation [106], and in an ethanol-induced animal model of alcoholic fatty liver disease, L-serine supplementation reduced hepatic neutral lipid accumulation and increased glutathione and S-adenosylmethionine levels [107]. In addition, in a mouse model of hepatic fibrosis, a common feature of most chronic liver diseases [143], L-serine supplementation reduced inflammatory cell infiltration, collagen deposition, and the extent of fibrosis in liver tissue [108]. Together, these findings underscore the beneficial role of both exogenous and endogenous serine in regulating hepatic lipid metabolism, thereby reducing the risk of age-related chronic liver diseases.

While the effects of serine on cardiovascular-related disorders have not been as well studied as other ARDs, there are promising preliminary results that suggest it may be a beneficial preventative or treatment for cardiovascular disorders. For example, an observational study identified an inverse relationship between serine concentration and coronary heart disease (CHD) in patients, suggesting a possible protective role of serine in CHD [144]. Furthermore, enhanced contractile function was observed in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with genetic dilated cardiomyopathy (DCM) following treatment with agents that activate the L-serine biosynthetic pathway [145]. Notably, serine supplementation was found to reduce methionine-induced elevation of plasma homocysteine concentrations, a known risk factor for cardiovascular disease, suggesting potential cardiovascular benefits of serine supplementation [146]. Others further demonstrated that activation of the serine and one-carbon metabolism pathway increases ATP levels causing improved cardiac function and attenuated pathological remodeling following pressure overload [15]. Also, significant antihypertensive effects of L-serine were found in a rat model of hypertension, noting that it promotes vasodilation in resistance arterioles and reduces mean arterial pressure [104, 105]. Overall, these findings suggest that L-serine may play a beneficial role in promoting cardiovascular health, but more hypothesis-directed studies are needed.

Serine metabolism has probably been most studied in cancers, and findings are often contradictory to the benefits for other ARDs. We will not delve deeply into the role of serine metabolism in antitumor immunity and cancer and only highlight a couple of findings, as these topics have been extensively discussed in previous reviews [1, 44]. For example, de novo serine production is frequently elevated across various cancer cell types [56], and some studies have suggested that serine supplementation may enhance tumor growth [147], raising concerns regarding its nutritional application in humans. Moreover, emerging evidence links serine metabolism to antitumor immunity, as serine may directly influence adaptive immune responses by regulating T cell proliferation and supplying one-carbon units necessary for de novo nucleotide biosynthesis in proliferating T cells [109]. Lipopolysaccharide (LPS) has been shown to activate the serine synthesis pathway and one-carbon metabolism, driving SAM production in macrophages [148]. Thus, serine is vital for the proliferation and differentiation of immune cells in antitumor immunity. However, given the reliance on serine in both tumor cells and immune cells, therapeutic strategies involving serine restriction, supplementation, or inhibition of serine biosynthesis may yield distinct outcomes depending on the cancer type. Therefore, long-term studies and appropriate experimental models are required to rigorously evaluate the effects of serine intervention in cancer treatment before such approaches can be considered for clinical application.

Serine metabolites and serine-linked metabolic pathways in aging

Evidence suggests that serine significantly influences organismal lifespan, not just as a metabolite but also through its downstream metabolic pathways. NADPH levels decrease with age across various tissues, and the overexpression of NADPH-synthesizing enzymes has been associated with extended lifespans in multiple biological models [149]. In addition, depletion of GSH has been linked to numerous adverse effects, including impaired immune function and increased vulnerability to oxidative stress [150]. A decline in GSH levels has been correlated with aging and various age-related diseases, including neurodegenerative disorders [151]. Conversely, older adults with excellent physical and mental health have been reported to have elevated GSH, suggesting that higher GSH concentrations may contribute to increased healthspan and lifespan [152].

Moreover, L-serine can be converted into glycine, and evidence suggests that glycine may function as a pro-longevity molecule. Supplementation of this amino acid has been demonstrated to extend lifespan across various model organisms, including worms, flies, mice, and rats [73, 153–155], and it enhances health outcomes by inducing autophagy and exerting anti-inflammatory effects [156–159]. Additionally, glycine acts as an acceptor in the methylation reaction catalyzed by glycine N-methyltransferase (GNMT), an enzyme whose overexpression has been shown to extend lifespan in flies [153, 160]. In mammals, GNMT plays a role in methionine clearance [161], and mice deficient in GNMT are predisposed to developing hepatocellular carcinoma and steatosis [162]. In addition, glycine supplementation has been reported to reduce plasma methionine concentrations and protect against methionine toxicity in rats [163, 164]. Similarly, glycine supplementation has been found to decrease methionine levels in C. elegans [73]. Thus, glycine may also improve health and extend lifespan by mimicking the effects of methionine restriction.

Additionally, serine contributes to the synthesis of S-adenosylmethionine (SAM), which can extend lifespan by activating adenosine monophosphate-activated protein kinase (AMPK). AMPK serves as a central regulator in numerous nutrient-responsive pathways linked to longevity [165, 166] and has been identified as a key modulator of aging across various organismal models [167, 168]. For example, the activation of SAM synthesis stimulates Snf1, the yeast ortholog of AMPK, leading to lifespan extension in Saccharomyces cerevisiae [169]. AMPK activation also has been shown to enhance mitochondrial function, promote fatty acid and cholesterol synthesis, and inhibit inflammation, all of which play critical roles in regulating cellular senescence [170]. SAM also serves as a precursor to S-adenosyl-L-homocysteine (SAH), which donates an aminopropyl group for the synthesis of spermidine [171]. Tissue levels of spermidine have been reported to decline with age in both humans and model organisms [172–174], and spermidine has been recognized as a significant geroprotective compound found in food [175]. Remarkably, spermidine has been shown to significantly extend the lifespan of worms, yeast, flies, mice, and human immune cells [174, 176–178]. A recent epidemiological study further supports a positive association between dietary spermidine intake and increased human healthspan and lifespan [179]. Spermidine functions as a well-tolerated caloric restriction mimetic, increasing autophagy and extending cellular lifespan [180]. Additionally, spermidine exerts direct antioxidant and metabolic effects on arginine bioavailability and nitric oxide production [178]. These health-promoting mechanisms collectively may contribute to lifespan extension across diverse organisms.

Furthermore, serine is converted to pyruvate by cytosolic serine dehydratase. In C. elegans, increased pyruvate levels mimic lifespan extension typically induced by dietary restriction (DR) [181]. Pyruvate also exerts protective effects against aging phenotypes by preventing senescence in normal human dermal fibroblasts, partly through the increased production of NAD + during its conversion to lactate, and pyruvate deprivation leads to cell senescence in these fibroblasts [182]. Dysregulation of pyruvate metabolism has been implicated in the pathogenesis of age-related disorders including cancer, heart failure, and neurodegenerative diseases [41]. Taken together, nutritional interventions targeting serine metabolism may promote human longevity by enhancing the production of these health-promoting metabolites through serine-related metabolic pathways or serine supplementation.

An indirect metabolite of serine biosynthesis, α-KG, produced by PSAT1, is also significantly associated with aging, as circulating α-KG levels decline with age [183], and α-KG supplementation has been linked with lifespan extension in various model organisms. For example, in C. elegans, dietary supplementation with α-KG has been associated with increased autophagy and extended lifespan, mediated by the inhibition of ATP synthase and the mTOR pathway [57]. Additionally, α-KG supplementation has been shown to reduce systemic inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and interleukin-6 (IL-6), and to extend lifespan in older mice [63].

While many serine metabolites appear to have beneficial effects in later ages, others, such as ceramides and sphingomyelin (SM), have been implicated in negative aging phenotypes. Ceramide, a central molecule in sphingolipid metabolism, has been shown to significantly accumulate in senescent cells [184]. Elevated ceramide levels are associated with mitochondrial dysfunction, oxidative stress, and the activation of pro-inflammatory pathways [53]. Furthermore, genetic disruptions in ceramide and sphingolipid synthesis pathways have been reported to extend lifespan in model organisms. For instance, RNA interference (RNAi)-mediated knockdown of the ceramide synthase gene hyl-1 increases lifespan in C. elegans [185]. Moreover, the loss of function of ceramide synthase genes hyl-1 and lagr-1 induces autophagy-dependent lifespan extension in worms [186]. Notably, exogenous ceramide has been found to cause a senescent phenotype in young human diploid fibroblasts [184]. Similarly, dysregulation of SM metabolism has been linked to neuroinflammation and neuronal cell death [187]. SM-ceramide signaling may play an important role in regulating cellular processes such as proliferation, differentiation, and survival, as well as modulating lifespan [188]. Given the diverse roles of serine metabolites and serine-linked metabolic pathways in aging, it is essential to investigate the specific mechanisms through which serine metabolism influences health and lifespan.

Concluding remarks and future perspectives

Traditionally regarded as a non-essential amino acid, serine has emerged as a significant, yet historically undervalued, component in aging research. Substantial progress has been made in elucidating the effects of serine on longevity and health across various model organisms, and the evidence for dysregulations of serine metabolism in neurological disorders and other age-related conditions suggests increasing serine levels may be a viable strategy to slow aging related phenotypes. The detailed examination of serine metabolism across diverse species in this review identifies critical targets for such serine interventions. Future studies that explore the combination of endogenous serine synthesis with exogenous dietary supplementation could lead to innovative therapeutic applications of serine, particularly in the context of aging and age-related diseases. Such advancements will deepen our understanding of serine as a functional amino acid and its broader implications for human health.

While the pro-longevity effects of L-serine are well-documented, some studies have produced conflicting results. For example, supplementation with D-serine, an enantiomer of L-serine, did not extend lifespan and even slightly reduced it at higher concentrations in C. elegans [74]. In yeast, inhibition of serine synthesis from 3-phosphoglycerate was shown to extend chronological lifespan [189], and serine may accelerate yeast aging by activating a phosphorylation signaling cascade involving Pkh1/2, Sch9 (the mammalian homolog of S6 kinase), and Rim15 protein kinases [190]. Furthermore, serine is involved in the production of sphingolipids such as ceramide and sphingomyelin, which have been implicated with mitochondrial dysfunction and impaired protein homeostasis, thus warranting further investigation.

Overall, a more comprehensive understanding of the mechanisms by which serine metabolism influences human pathologies associated with aging is essential. Future research should aim to elucidate the molecular mechanisms through which serine metabolism supports animal and human health, thereby enabling the development of therapeutic strategies targeting the serine metabolic pathways.

Funding

This work was funded by R00AG059920 to JMH. The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declarations

Conflict of interest

The authors declare no competing interests.