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Epigenetic regulation of caloric restriction in aging

Yuanyuan Li13*, Michael Daniel1 and Trygve O Tollefsbol12345

Author affiliations

1 Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA

2 Center for Aging, University of Alabama at Birmingham, 1530 3rdAvenue South Birmingham, AL 35294, USA

3 Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, 1802 6th Avenue South, AL 35294, USA

4 Nutrition & Obesity Research Center, University of Alabama at Birmingham, 1675 University Boulevard, Birmingham, AL 35294, USA

5 Diabetes Comprehensive Center, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA

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Citation and License

BMC Medicine 2011, 9:98  doi:10.1186/1741-7015-9-98


Received:6 May 2011
Accepted:25 August 2011
Published:25 August 2011

© 2011 Li et al; licensee BioMed Central Ltd.




caloric restriction; epigenetic; aging


Aging and its direct consequences, such as degenerative diseases and even death, are inevitable; however, scientific advances in understanding basic aging mechanisms have made it much more feasible to postpone aging processes and to increase the human lifespan using clinical approaches. Current studies using model organisms indicate that aging processes can be manipulated by many interacting factors which include, but are not limited to, geneticnutritional and pharmacological interventions [1-3]. Studies of monozygotic twins, who share the same genotype and often present many phenotypic differences [4-7], indicate that external environmental factors contribute to interindividual differences such as susceptibility to disease and the potential to live longer.

Dietary control, as a major environmental factor, has a profound effect on many aspects of health, including aging, and caloric restriction (CR) is by far the most effective environmental manipulation that can extend maximum lifespan in many different species [8,9]. In fact, the remarkable effect of CR on aging was first defined in experimental animal models in which McCay et al. [10] discovered that rats fed a calorie-restricted diet lived longer than control rats fed a regular diet. Since then, numerous research findings have revealed effects of CR on lifespan interference among diverse, but not all eukaryotes, including yeast, worms, flies, fish and even mammals [11-13]. In most rodent CR studies, the limitation of total calories derived from carbohydrates, fats or proteins to a level 25% to 60% below that of control animals fed ad libitum, while containing all essential nutrients [14-16], can result in a significant lifespan extension in 50% of rodents [17-21]. In addition to increasing lifespan in rodents, CR has also been shown to delay a wide range of aging-associated diseases, such as cancer, diabetes, atherosclerosis, cardiovascular diseases and neurodegenerative diseases in higher mammals, such as nonhuman primates and humans [13,22-24] (Table 1). The incidence of disease increases with age and is a fundamental contributor to mortality. Thus, CR may affect aging processes by favorably influencing broad aspects of human health.

Table 1. Summary of aging-related diseases affected by caloric restriction in experimental animal models and clinical trialsa

Numerous studies suggest that the effects of CR in the prevention of the onset of many aging-related degenerative diseases occur through various molecular mechanisms, including reduction of oxidative stress or regulation of metabolic pathways during the progression of aging [14,25,26]. However, the precise mechanisms of CR-induced longevity are not very well understood. Recently, epigenetic mechanisms have received considerable attention due to the unique role of interactions with multiple nutritional factors and the aging processes. Epigenetic control is believed to dynamically regulate gene expression by mechanisms other than changes in the DNA sequence. This primarily affects two epigenetic codes: DNA methylation and histone modification [27-29]. Recent evidence suggests that DNA methylation status changes in specific gene loci may play an essential role in CR-dependent aging postponement and longevity [30,31]. More concrete evidence has emerged, most notably the discovery of silent mating type information regulation 2 homolog 1 (Sirtuin 1), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (HDAC), since Sirtuin 1 activity has been linked to the control of lifespan in response to CR both in vivo and in vitro [32-36]. Although studies of the characterization and function of epigenetic modifications in CR-associated longevity are just emerging, a better understanding of this complex interaction provides promising clinical opportunities for the prevention of human aging and degenerative diseases that often accompany the aging process.

DNA methylation affects aging during caloric restriction



Table 2. Selected genes regulated by epigenetic factors during caloric restrictiona



thumbnailFigure 1. Caloric restriction regulates epigenetic pathways. Caloric restriction (CR) influences epigenetic processes via two primary mechanisms: DNA methylation and histone modification. DNA methylation regulation during CR involves DNMT activation, resulting in silencing the expression of target genes such as p16INK4a and Ras due to hypermethylation of these genes. CR-induced histone remodeling primarily includes histone acetylation and methylation. Deacetylation effects due to activation of SIRT1 and HDAC1 by CR lead to expression changes of key genes such as p53, Foxo, Ku70, PGC-1α and p16INK4a. Histone methylation also plays a role in the regulation of key gene expression, including hTERT and p16INK4a. As a result, epigenetic regulation actively reverses aberrant gene expression during CR, which contributes to CR-associated aging delay and lifespan extension.



Table 3. Epigenetic clinical trials for aging-related degenerative diseasesa



Effects of histone remodeling in control of aging during caloric restriction



Histone acetylation and deacetylation


In addition to their deacetylation function, HDACs are believed to participate in the regulation of many cellular functions and gene expression through interactions with hundreds of different transcription factors [71,73]. It has also been reported that HDAC activity is increased during CR, suggesting that global deacetylation may be a protective mechanism against nutrition stress and may influence the aging processes [31].

We have found that altered binding enrichment of HDAC1, such as on the promoter regions of the p16INK4a and human telomerase reverse transcriptase (hTERT) genes, the latter of which is a key determinant of telomerase activity closely associated with aging regulation, leads to beneficial expression changes of these two genes and contributes to longevity under CR conditions (Figure 1 and Table 2) [31,74,75]. Therefore, remarkable roles of the HDAC family in regulation of aging during CR highlight the potential application of related epigenetic drugs or clinical strategies in aging and aging-related diseases.

At this point, HDAC inhibitors have emerged as an exciting new class of potential anticancer agents despite little evidence pertaining to other aging-related diseases. HDAC inhibition causes acetylation of nuclear histones, leading to transcriptional activation of several key tumor-related genes, such as the cyclin-dependent kinase inhibitor p21WAF1/CIP1, p53, GATA-1 and estrogen receptor-α, which contribute to inhibiting cancer proliferation and inducing differentiation both in vitro and in vivo [76,77]. Several HDAC inhibitors with impressive antitumor activity and relatively low toxicity, such as depsipeptide, phenylbutyrate, valproic acid and suberoylanilide hydroxamic acid, are currently undergoing phases I and II clinical trials (Table 3) [78,79]. These structurally diverse molecules with properties of HDAC inhibition support a model in which HDACs are the critical cellular targets causing chromatin instability and tumorigenesis. Bioactive dietary ingredients, such as green tea polyphenols, broccoli sprouts and soybean genistein, that have natural HDAC inhibition properties are also considered as potential cancer chemoprevention compounds which are being studied in preclinical trials (Table 3) [62,63,80]. This may apply to aging-associated degenerative diseases that involve similar abnormalities such as tumorigenesis, and further studies are urgently needed in this area.

Sirtuin 1 and its substrates



In mammals, SIRT1-null mice do not survive longer, and most of them die during the postnatal period [86,87]. They exhibit growth retardation, multiple developmental defects and sterility, suggesting an important role of SIRT1 in early development. The role of endogenous SIRT1 in mammalian metabolic regulation has focused mainly on rodents in the context of fasting under the condition in which SIRT1 overexpression or its activity is upregulated [33-36]. Extensive studies have shown that CR induces SIRT1 expression in several tissues of mice or rats [33]. The potential mechanisms by which SIRT1 mediates CR-induced metabolic alterations and subsequent aging retardation primarily involve two aspects: first, SIRT1 activation increases stress resistance by negative regulation of proapoptotic factors such as p53 and Foxo (Table 2) [88-92]; second, SIRT1 causes a series of endocrine responses, including inhibition of adipogenesis and insulin secretion in pancreatic β cells by regulation of key metabolism-associated genes such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (Table 2) [93,94], which facilitates stress resistance and longevity (Figure 1).


Although classed as a HDAC, SIRT1 deacetylates a broad range of substrates, including many nonhistone substrates [33,83] (Table 2 and Figure 2). These potential substrates may include several key transcription factors and regulatory proteins that are involved in multiple pathways linked to physiological and metabolic processes that contribute to lifespan extension by CR (Table 2 and Figure 1). CR is known to exert its effect by inhibition of apoptosis, which is one of the most important regulatory mechanisms [14,25,26]. In this regard, p53 is notable due to its important role in the regulation of cell death and apoptosis. Downregulated p53 by SIRT1 deacetylation may affect lifespan by negatively regulating cellular apoptosis and replicative senescence processes [88-90]. Another important protein that influences apoptosis is Foxo. Foxo protein can be directly deacetylated by SIRT1 at lysine residues and its expression is reduced, thereby repressing Foxo-mediated apoptosis [91,92]. In addition, the DNA repair protein, Ku70, can become deacetylated by SIRT1, allowing it to inactivate the proapoptotic factor Bax, resulting in apoptosis inhibition [99,100].

SIRT1 can also regulate the expression of genes that are involved in metabolic pathways. PGC-1α represents the best example of these proteins in CR studies (Table 2). PGC-1α is a key regulator of gluconeogenesis and fatty acid oxidation [93,94]. It is activated by SIRT1-mediated deacetylation, which increases its ability to coactivate HNF4α, a transcription factor that promotes the expression of gluconeogenic genes and represses genes involved in glycolysis [34,83]. Therefore, SIRT1-induced changes in PGC-1α expression, and its downstream metabolic pathways provide a link between SIRT1 activation and the stimulation and response of metabolic systems under CR conditions.

Another key gene that can be epigenetically regulated by SIRT1 is p16INK4a, which is a cyclin-dependent kinase inhibitor linked to cellular senescence regulation [101] (Table 2). This gene was originally identified as an important tumor suppressor gene in that it negatively regulates the cell cycle and inhibits tumor growth [102,103]. Current studies show that p16INK4a is significantly accumulated during the aging processes, indicating that p16INK4a can serve as a robust aging biomarker [104,105]. Our recent studies using human cells show that CR-activated SIRT1 can directly bind to the p16INK4a promoter and decrease its expression through a deacetylation effect, which contributes to delaying the aging process and to lifespan extension [84]. Therefore, SIRT1, acting as a nutrition sensor, decodes the nutrition flux to ensure homeostasis or even a beneficial state such as increased longevity by reorganizing the global chromatin structure and dynamically epigenetically regulating specific genes that may involve apoptosis regulation, metabolic control and cellular senescence. Besides its pronounced roles in regulating epigenetic processes, SIRT1 has been well demonstrated to regulate genes and interact with signaling other than epigenetic control during CR, suggesting that SIRT1 may play an important role in multiaspect cross-talk between epigenetic and genetic pathways.

Histone methylation

Besides histone acetylation, histone methylation is another important histone modification that regulates gene expression [72] (Figure 2). In contrast to histone acetylation, which is always associated with open chromatin status and subsequent gene activation, differentially methylated forms of histones show unique association patterns with specific proteins that recognize these markers and thus lead to gene silencing or activating effects. Lysine residues on histones can be mono-, di- or trimethylated, and either activation or repression is dependent upon the particular lysine residue that is modified [106,107]. Our current studies have shown that histone methylation modifications such as di- or trimethylated histone H3 at lysine residue 3 or 4 can also regulate expression changes of key aging-related genes, including p16INK4a and hTERT, thereby contributing to CR-induced lifespan extension of human cells (Figure 1 and Table 2) [31,84]. In other studies, researchers have reported that p16INK4a expression can be regulated by H3K27 trimethylation, which serves as a recruitment signal for BMI1-containing polycomb-repressive complexes such as PRC1 during cellular senescence [108-110]. Therefore, the status of specific histone methylation can also serve as a transcription modulator by interacting with different transcription factors and regulate aging processes under CR conditions.

Potential epigenetic treatments for aging-related diseases








bp: base pair; CR: caloric restriction; DNMT: DNA methyltransferase; HDAC: histone deacetylase; HAT: histone acetyltransferase; hTERT: human telomerase reverse transcriptase.

Competing interests

The authors declare that they have no competing interests.

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Pre-publication history
