1. INTRODUCTION:

Over the course of life, the physiological and biological capabilities to repair and rejuvenate decrease, and often, this complex phenomenon is called aging. This can lead to deteriorating physiological integrity and functionality, raising mortality and susceptibility to age-related disorders such as diabetes, cancer, heart disease, and neurological disorders¹. SIRT1 a nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylase, is the human counterpart of the yeast silent information regulator 2 and a crucial metabolic sensor that reacts to the energy state of cells². Sirtuins, class III histone deacetylases, are divided into seven varieties; SIRT1 has been investigated in humans more than the other categories. It is found in various tissues, such as the liver, pancreas, muscles, adipose tissues, and the brain. Sirtuin 1 plays a significant role in controlling cellular senescence and the lifespan of organisms by changing the transcriptional, enzymatic, and protein levels of these substrates through acetylation and deacetylation. Reduction in sirtuins expression can lead to the development of many human illnesses, including neurodegenerative disease, cardiovascular disease, non-alcoholic fatty liver disease, and cancer³. Sirtuins are excellent anti-aging targets because they are essential for DNA repair, inflammatory regulation, and antioxidant protection⁴.

Vitamin D insufficiency is associated with cardiovascular diseases, autoimmune disorders, infectious diseases, cancer, diabetes, and other conditions^5,6,7,8. Numerous research has demonstrated that vitamin D affects several biological processes, including immunological modulation, neurogenesis, cell proliferation, differentiation, apoptosis, and genomic sequences. People are far more likely to become vitamin D deficient as they age. In recent years, studies have reported that low serum vitamin D levels are one of the common nutritional deficiencies in India. It has been reported in South Karnataka, India, that the prevalence of vitamin D insufficiency and deficiency is high across all age groups in both genders^6,7,9,10. Vitamin D may influence biological aging by modulating the expression and polymorphism of Sirtuin 1 and activates various substrates that promote DNA repair, mitochondrial function, and anti-inflammatory pathways. This relationship highlights the potential of vitamin D as a nutrient essential for bone health and as a modulator of longevity and age-related health conditions¹¹.

Furthermore, vitamin D can potentially elevate the activity of human endothelium SIRT1, which is reversible by hydrogen peroxide. SIRT1 is found to be essential vitamin D enhanced VDR-SIRT1 interaction, activation, and auto-deacetylation. This happens despite elevated cofactor (NAD+) concentrations and elevated SIRT1 RNA and protein expression^11,12,13. However, limited evidence is available regarding the potential link between vitamin D deficiency and SIRT1 gene polymorphism and its expression in the middle-aged population. Therefore, this study evaluated SIRT1 gene polymorphism and expression as molecular biomarkers of biological aging in relation to vitamin D levels in the middle-aged population.

2. METHODOLOGY:

2.1 Study participants and data collection:

The study sample consisted of 200 participants, out of which 174 participants were enrolled in the study. The central ethics committee of the institute approved the study protocol. Subjects were chosen based on the inclusion criteria of age group 45 to 65 years and subjects with vitamin D levels (30-100ng/ml)¹². Patients with hypertension, Diabetic Mellitus, Chronic Kidney disease, Liver cirrhosis, acute inflammatory-infectious illness, and patients who were on vitamin D supplements were excluded from the study. The recruited participants were monitored by clinicians in the outpatient department of the tertiary hospital. The study protocol was explained to each participant in detail, and written content was obtained. Further, 5ml blood sample was collected by antecubital vein under a sterilized atmosphere for further analysis.

2.2 Blood Sample Analysis:

Serum sirtuin1 (Krishgen Biosystems, India) and vitamin D levels (J.Mitra Pvt. Ltd, India) were estimated by using ELISA- an enzyme-linked immunosorbent assay as per instructions given by the manufacturer. The concentration of each sample was measured in duplicates¹⁵.

2.3 Extraction of DNA:

The blood sample was kept at room temperature, and 7 ml of blood RBC Lysis buffer solution and two ml of sample were added to the lysate. The entire mixture was centrifuged for five minutes at 3500rpm, the supernatant was discarded and inverted in the tube for 30minutes. A vortex was done to suspend the cells. 2ml of WBC Lysis solution buffer was added, and the vortex was done. The solution was left to stand at room temperature for two - four hrs until it became homogenous, 0.7ml of protein precipitation was added to the solution after vertexing for 20 secs and centrifugation was done for 10 minutes at 3000rpm. 2ml isopropanol was added to other centrifuge tube and supernatant were dumped into new tube; the mixture was shaken for 50-60 times to observe a thread-like structure. Centrifugation was done for 3mins at 3000rpm and discarded the supernatant was 70% ethanol- 4ml was used to wash pellets, and centrifuged at 3000rpm for two minutes. Tubes were dried overnight, and 50μl of tris EDTA Buffer was added and kept for two to three hours at room temperature; as soon as the DNA was dissolved, it shifted into Eppendorf tubes and kept at -20℃¹⁶.

2.4 SIRT 1 Genotyping:

Genotyping was carried out by PCR-RFLP. Single nucleotide polymorphisms (SNP), rs3740051, were analyzed from extracted DNA by using specific forward and reverse primers using primer 3 plus software to choose specific primers^16,17. Genotyping of SIRT1 rs3740051 polymorphism was carried out with the forward primer 5’- GGAGGGAATTCACACACGTT-3’ and the reverse primer 5’-CTGGCCTGCCTTAGCCTTGTCT-3’¹⁰. Following was the PCR condition: initial denaturation at 9℃ for 5 mins, followed by 35 cycles of denaturation at 95℃ for 30 secs, annealing temperature at 62℃ for 30 secs, and the extension at 72℃ for 1 minute, followed by final extension at 72℃ for 5 mins. 379bp fragments were obtained, and it was digested with restriction enzyme-Hpa1 (0.5μl) overnight at 37℃ and separated by using agarose gel (3%) with ethidium bromide¹⁸.

2.5 Statistical Analysis:

Continuous data is presented as the mean±SD, and categorical data is presented as a percentage. Serum sirtuin 1 level between the two study groups was compared using the Mann-Whitney U test. Spearman's correlation was used to correlate vitamin D levels with sirtuin 1 levels. The association between genetic polymorphism and vitamin D levels was assessed using the Chi-square test. All the statistical analysis was performed using the SPSS 25^th version software. The Hardy-Weinberg test was performed to check the frequency pattern of the SIRT1 gene.

3. RESULTS:

Among 174 participants, 87 were recruited in the vitamin D deficient group and another set as the vitamin D sufficient group after vitamin D analysis. The descriptive statistics were performed on variables like age, weight, BMI, Resting Heart Rate, Systolic Blood Pressure, Diastolic Blood pressure, and serum vitamin D level. (Table 1). Table 2 shows a significant correlation between vitamin D levels and sirtuin 1 levels (r=0.998, p=0.001). Table 3 displayed frequencies of genotypes in the SIRT1 gene in all the groups. CC, CT, and TT genotype frequencies of rs3740051 were 46%, 16%, and 13% respectively in the vitamin D deficient group and 57%,14%, and 3% in controls respectively.

Table 1: Descriptive data of the study population (N=174)

Variables	Vitamin D deficient group (N=87)	Vitamin D sufficient group (N=87)
Age (Years)	52.13 ± 4.16	51.05±8.01
Weight (kg)	63.01 ±7.86	64.08±8.56
BMI (kg/m²)	25.43 ± 3.26	24.75±3.96
RHR (bpm)	80 ± 84	80±80
SBP (mmHg)	120 ± 130	120±130
DBP (mmHg)	80 ± 90	80±80
Vitamin D levels (ng/ml)	16.50 ± 3.56	34.33±3.51

Data is denoted as Mean±SD.

Abbreviations: BMI- Body Mass Index, RHR- Resting heart rate, SBP- Systolic Blood Pressure, DBP- Diastolic Blood Pressure

Figure 1: Bar plot showing a difference in Sirtuin 1 level in controls with vitamin D deficient group. The graph is generated using GraphPad Prism 8.0

Analysis was done using Mann Whitney U test

Data expressed as mean±SD

***p-value < 0.0001 considered statistically highly significant

Table 2: Correlation of Vitamin D levels with Sirtuin 1 levels.

Vitamin D levels

R-value

p-value

Sirtuin 1 levels

0.998

0.001**

Association was done using Spearman’s correlation Test

R―indicates strength of correlation.

**p value < 0.001

Table 3: Pattern of SIRT 1 gene polymorphism in vitamin D deficient and normal vitamin D groups

Group	Genotype	Frequency	Percentage
Vitamin D deficient group (N=87)	CC	53	46.11 %
	CT	19	16.53 %
	TT	15	13.05 %
Vitamin D sufficient group (N=87)	CC	66	57.42 %
	CT	17	14.79 %
	TT	4	3.48 %

SNP rs3740051

Table 4: Hardy Weinberg Equilibrium for SIRT1 gene among subjects with Vitamin D Deficiency

Gene variant

Frequency of pattern in SIRT1 gene

Common homozygotes

Observed

Expected

Heterozygotes

Observed

Expected

Rare Homozygotes

Observed

Expected

Chi-square value 18.4

p-value 0.000018

p≤ 0.05, df = 4, wpcalc online calculator used.

The Hardy-Weinberg Equilibrium for the SIRT1 gene variant in vitamin D deficient group revealed a notable discrepancy between observed and expected frequencies across common homozygotes, heterozygotes, and rare homozygotes (table 4). Observed frequencies differ significantly from expected frequencies, as indicated by a Chi-square value of 18.4, yielding a p-value of 0.000018. This discrepancy suggests that the SIRT1 gene variant deviates from Hardy-Weinberg Equilibrium, indicating potential factors such as genetic drift, selection pressure, or population migration influencing allele frequencies within the gene pool.

Table 5: Hardy Weinberg Equilibrium for SIRT1 gene in healthy Controls

Gene variant

Frequency of pattern in SIRT1 gene

Common homozygotes

Observed

Expected

Heterozygotes

Observed

Expected

Rare Homozygotes

Observed

Expected

Chi-square value 3.6

p-value 0.05778

p≤ 0.05, df = 4, wpcalc online calculator used.

In the control group, the Hardy-Weinberg Equilibrium analysis for the SIRT1 gene variant demonstrates relatively closer alignment between observed and expected frequencies across common homozygotes, heterozygotes, and rare homozygotes (table 5). Despite a Chi-square value of 3.6, suggesting some deviation from the expected frequencies, the associated p-value of 0.05778 indicates a marginal significance. This implies that while there may be minor discrepancies between observed and expected frequencies, the SIRT1 gene variant in the control group appears to approximate Hardy-Weinberg Equilibrium, suggesting that external factors such as genetic drift or selection pressure may have a lesser impact on allele frequencies within this population subset.

Figure 2: PCR-RFLP results of rs3740051: 1-17 show wild type (C/C genotype) and 18,19 shows carrier (C/T genotype). 50bp (base pair) ladder was used.

4. DISCUSSION:

Vitamin D deficiency is recognized as one of the most common nutritional deficiencies globally. Apart from calcium homeostasis, vitamin D is linked with various mechanisms associated with anti-aging function. This study aimed to evaluate whether serum vitamin D levels modulate the expression and polymorphism of the SIRT1 gene, one of the molecular hallmarks of biological aging.

The role of SIRT1 gene polymorphism in vitamin D deficiency is a developing field of study that has great potential for gaining insight into the genetic elements influencing the onset and course of age-related diseases such as bone metabolic disorders, diabetes, tumors, and cardiovascular diseases; also, it increases the risk of autoimmune illnesses and mental disorders¹⁵. vitamin D insufficiency is characterized by conditions such as rickets in children, Osteomalacia, hypophosphatemia, or hypocalcemia in adults¹³. The sirtuins gene, particularly SIRT1, has been recognized as a potential participant in these processes. Finding out more about the genetic diversity in this gene can provide important insights into the etiology of vitamin D insufficiency^18,19.

The present study found a significantly higher serum Sirtuin1 expression in the vitamin D sufficient group compared to the deficient group (fig.1). Higher Sirtuin 1 expression in the vitamin D sufficient group indicates that the vitamin D is an epigenetic regulator for activation of Sirtuin 1. Previous research done by Chandel N et al., has shown similar results and our findings are in line with it¹⁹. vitamin D acts on many levels to activate the epigenetic regulator SIRT1 through the facilitation of auto-deacetylation; post-translationally, ligand-activated VDR increases SIRT1 activity^11,18.

Further, this study also observed a significant correlation between vitamin D levels and sirtuin 1 levels, suggesting a potential mechanism by which vitamin D may influence the aging process and overall health. Studies suggest that vitamin D can upregulate the expression of SIRT1 by enhancing the transcriptional activity at the SIRT1 promoter. SIRT1 enhances DNA repair mechanisms and maintains genomic stability. vitamin D’s role in increasing SIRT1 expression supports these protective effects. SIRT1 activation leads to increased mitochondrial biogenesis and function, critical for energy production and reducing oxidative stress. vitamin D’s role in upregulating SIRT1 supports mitochondrial health, essential for aging cells²⁰.

The deviations from Hardy Weinberg Equilibrium observed in both vitamin D deficient subjects (Table 4) and healthy controls (Table 5) suggest potential factors influencing allele frequencies within these populations. Population stratification, genetic drift, selection pressure, or migration patterns may contribute to these deviations, highlighting the importance of considering population dynamics in genetic association studies.

The differences in SIRT1 gene polymorphism between vitamin D deficient subjects and controls (subjects with normal vitamin D levels) suggest a potential genetic predisposition to vitamin D deficiency. Variants in the SIRT1 gene, rs3740051, may further influence vitamin D metabolism or signaling pathways, affecting individuals' susceptibility to deficiency.

The SIRT 1 controls transcription factors, transcriptional coactivator p300, and DNA repair factor Ku70, which appear to be involved in the generation of proinflammatory cytokines; thus, it regulates various physiological functions, including inflammation and cell survival¹⁷. It directly decreases the generation of cytokines that promote inflammation and prevent apoptosis¹⁸. The results of this study show that vitamin D-bound VDR upregulates SIRT1 expression and interacts with SIRT1 to initiate auto-deacetylation on Lys610 and catalyze the activity of SIRT1^21,22.

Auto-deacetylation of SIRT1 is triggered by both SIRT1 and vitamin D. Together with higher mRNA and protein levels and an increase in cofactor (NAD+) availability, the relationship between SIRT1 and vitamin D insufficiency is expanded by the discovery that 1,25(OH)2D3 stimulates SIRT1 at several levels, including gene expression and activity²⁴. Since SIRT1 target proteins regulate multiple processes, including mitochondrial physiology, apoptosis, and inflammation, the capacity of vitamin D to activate SIRT1 may have significant effects on physiological and pathological processes²⁵. As a result, vitamin D may have a secondary effect on various events and processes by controlling SIRT1 activity and directly regulating gene expression via transcriptional regulation of VDR-bound targets^26,27,28.

This study also found a significant association between genotypic distribution and vitamin D level in vitamin D deficiency subjects (table 6), similar to the study done by Sabir MS et al. The SIRT1 gene has an upstream transcription variation called SNP rs3740051 (C>T). The vitamin D deficient group had greater frequencies of the mutant (TT) allele of this SNP compared to the control, which indicates that rs3740051 may have a preventive effect on the development of vitamin D deficiency^29,30,31,32. However, the molecular mechanism of how the rs3740051 controls the vitamin D levels is unknown.

The findings underscore the clinical relevance of understanding the genetic basis of vitamin D deficiency and its association with SIRT1 gene polymorphism. Identifying individuals at higher genetic risk for vitamin D deficiency may inform targeted interventions, personalized treatment strategies, and preventive measures to mitigate the adverse health effects of vitamin D insufficiency.

Therefore, this study's findings indicate notable differences in SIRT1 gene variant distributions between vitamin D-deficient individuals and controls, suggesting a potential genetic predisposition to deficiency. Further, significant associations were observed between specific gene variants and vitamin D deficiency. Additionally, deviations from Hardy Weinberg Equilibrium in both deficient and control populations underscore the influence of population dynamics on allele frequencies. These findings highlight the complex interplay of vitamin D deficiency risk and modulation of genetic variation and protein expression of the SIRT 1 gene, thereby influencing the biological age.

5. CONCLUSION:

The study demonstrates that vitamin D deficiency is associated with higher SIRT1 gene polymorphism and lesser expression among middle-aged adults. Therefore, the study concludes that vitamin D might significantly influence biological aging by modulating the expression and polymorphism of SIRT 1 in middle-aged adults. Further, the outcomes of this study would provide deeper insights into the mechanisms of aging and dietary interventions and therapies for successful aging.

6. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

7. ACKNOWLEDGMENTS:

The authors would like to thank Nitte (Deemed to be University) and Central Research Laboratory for the support in conducting the research.

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Received on 31.08.2024 Revised on 06.02.2025

Accepted on 25.04.2025 Published on 01.12.2025

Available online from December 06, 2025

Research J. Pharmacy and Technology. 2025;18(12):5663-5668.

DOI: 10.52711/0974-360X.2025.00818

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.