New research uses an epigenetic approach to understand the impact of nutrition and physical exercise on aging.
Aging is a complicated business that is caused and accelerated by a variety of factors including genetics, the environment and lifestyle. Manifesting as a gradual decline in normal physiological functions, aging leads to a reduced capability to respond to stressors that in turn impact mortality and morbidity. Aging increases the susceptibility of people to several diseases such as cardiovascular disorders, metabolic disorders, cancer and neurodegenerative diseases [1], and yet, despite many studies on aging, it is still not understood clearly.
An increase in human lifespan over the last seven decades has resulted in a whopping increase in the population of individuals over age 60 – from 205 million in 1950 to 1 billion in 2019. As per prediction the by the World Health Organization (WHO), individuals over 60 years of age will outnumber children younger than 10 years of age by 2030 [2]. Although this increase in lifespan is attributed to developments in medicine, health, education, and sanitation; it also puts pressure on societies to develop special policies and services for the elderly.
WHO has termed the decade of 2020–2030 as the Decade of Healthy Aging, defining ‘healthy aging’ as the possibility for people to do or be what they value throughout their life. This suggests being independent and capable of participating in daily activities for older adults. Several longevity strategies are available for the improvement of healthy aging which include regenerative medicine, lifestyle modification, manipulation of genes and pathways associated with longevity, pharmacological compounds and tissue or organ engineering.
Additionally, genomic instability and epigenetic alterations are also reported to be potential targets for healthy aging interventions. Previous research highlighted several genes such as Forkhead box O 3 (FOXO3), insulin or insulin-like growth factor 1 (IGF-1), and AMP-activated protein kinase (AMPK) played essential roles in aging and could also serve as drug targetable for promoting healthspan. Many recent studies have also reported that epigenetics play an important role in the aging process.
Longevity.Technology: Epigenetics can be defined as reversible heritable mechanisms that affect gene expression through chromatin modifications without causing any changes in the underlying DNA sequences. The fundamental recipe stays the same, but instructions and interpretations get tweaked with the passage of time – DNA methylation works rather like those Post-It notes added to a cookery book
The eukaryotic DNA is condensed into a high-order chromatin which contains repeating structural units known as nucleosomes [3]. Each nucleosome comprises a histone octamer which includes two of each core histone proteins, surrounding which 147 base pairs of DNA are wrapped. Nucleosomes are arranged on the DNA as ‘beads on a string’ with a distance of about 200 base pairs between ‘beads’. This open DNA conformation is termed ‘euchromatin’ while the closed conformation is termed ‘heterochromatin’. Heterochromatin protects the DNA from damage, an ability which is gradually lost with age.
Histone modifications and heterochromatin decline
Post-translational modifications (PTMs) on histones have several effects on gene expression. There are over 20 post-translational histone modifications few of which include phosphorylation, acetylation, methylation, sumoylation and ubiquitylation (that last one gets everywhere). Histone modifications occur in the flexible N-terminal histone tails or other histone domains.
Moreover, some histone variants have been reported to replace some of the core histones during aging which in turn changes the chromatin architecture.
Methylation and acetylation are the two most studied PTMs that most often occur in the arginine and lysine residues of the histone tail. Aging has been reported to be associated with an increase in histone acetylation. Sirtuins, a group of histone deacetylases that belong to a family of NAD+-dependent proteins have been targeted by many studies to improve healthspan. Members of the Sirtuin family (SIRT), SIRT3, SIRT1 and SIRT6 have been observed to improve health and longevity in several model organisms, and this means that sirtuins are considered to be potential therapeutic targets for the extension of healthy aging [2].
Several specific PTMs have also been reported to be associated with aging such as H4K16ac, and aging has also been reported to be associated with a reduction in core histone proteins as well as protein synthesis. The loss of histone proteins has been associated with cellular senescence, aging, as well as increased genomic instability.
DNA methylation
DNA methylation (DNAm) has been reported in all eukaryotes and is key to embryonic development and cell differentiation. Methylation most commonly occurs at genomic locations rich in cytosine-guanine dinucleotides, known as CpG islands but can also occur in other nucleotide pairs. Additionally, DNAm is reported to be more common in heterochromatin as compared with euchromatin [2], and can take place either actively or passively. Passive demethylation occurs spontaneously while active demethylation is brought about by ten-eleven translocation (TET) proteins.
Eukaryotic DNA is hypermethylated at repetitive regions of the genome at young stages of life which contributes to genomic stability. However, global hypomethylation is reported to take place with age which results in impaired maintenance of DNAm patterns. Hypomethlaytion can take place at promoters of genes that regulate senescence which in turn can lead to their increased expression and accelerate aging. DNAm can also be used as a biomarker for the measurement of aging through analysis of methylation status across a large set of CpG sites.
Non-coding RNAs
Non-coding RNAs (ncRNAs) are important for controlling gene expression since they play important roles in biological and physiological processes. Circulating ncRNAs, especially microRNAs (miRNAs) are considered to be important biomarkers for studying aging and age-associated processes. LncRNAs or ‘long non-coding RNAs’ are another class of ncRNAs that are longer than 200 nucleotides. They have been reported to bind to RNA, DNA, or proteins and play a role in the post-translational as well as post-transcriptional regulation of gene expression.
Both these ncRNAs have been reported to impact inflammation-related pathways and senescence. miR-28e3p and miR-126 are two common ncRNAs that have been observed to influence aging, and research is undergoing on a few other ncRNAs as a potential targets for antiaging therapy.
Impact of nutritional and lifestyle strategies on epigenetics
There are myriad theories on how to extend a healthy lifespan – these include following fad diets, fasting, eating superfoods, supplementing and adopting specific behavioral habits. A few such practices, such as caloric restriction, have been observed to show promising results in scientific studies. Lifestyle factors that can impact epigenetic age and healthspan include literacy, stress levels, living environment, economic power and social network of an individual. Alcohol, lack of sleep, lack of exercise, poor diet and smoking have also been reported to be associated with accelerated aging.
Impact of nutrigenomics on healthspan
Nutrigenomics is defined as the study of diet and nutrients as well as their impact on the epigenome. Several theories suggest that many foods and diets can impact healthy aging, and research has highlighted that Mediterranean and Okinawan diets are associated with decreased risk of cardiovascular disease and a lower risk of cancer. Both these diets comprise low glycemic index foods, including consumption of seasonal and local foods, as well as consumption of moderate amounts of animal protein. Studies have also reported that these diets can reduce epigenetic age.
Research on superfoods such as curcumin, kale, algae and olive oil along with vitamins, polyphenols, and anti-oxidants is ongoing, to determine their impact on epigenetics.
Caloric restriction
Caloric restriction (CR) is defined as a reduction of the caloric intake of an individual by 10 to 40 percent without changing nutritional value. CR has been reported to have a significant impact on the lifespan and health of several model organisms from yeasts to mice, as well as humans. CR increases DNA repair, delays neurodegeneration, reduces the incidence of cancer and diabetes, improves glucose metabolism, as well as reduces epigenetic aging-associated events [2]. CR exerts its impact through nutrient-sensing pathways, and, in turn, leads to a decrease in protein synthesis and an increase in autophagy, as well as an increase in fatty-acid oxidation and ketogenesis. CR can lead to weight loss which reduces the risk of age-associated diseases.
At the epigenetic level, CR has been reported to delay DNAm age-related alterations and reduce histone modifications. However, CR is not easy to adopt which led to the development of intermittent fasting that could reap some benefits of CR, although its health benefits are not very clear. Moreover, CR can have several negative effects such as extreme weight loss, infertility and cognitive impairment. This led to the development of pharmaceutical agents that had the benefits of CR, and a few of these agents include NAD+ precursors, metformin and rapamycin.
Impact of physical exercise on epigenetics
Physical exercise is another important strategy to extend healthspan. Previous studies have indicated that a slight increase in physical activity can reduce age-associated conditions and inflammation. On an epigenetic level, regular physical activity has been shown to slow DNAm age-related alterations and bring about beneficial changes in miRNA.
It’s still diet and exercise – for now
Balanced nutrition, caloric restriction and physical exercise can impact aging as well as its associated epigenetic changes, and these longevity pillars are capable of promoting healthy aging and improving the longevity of people. However, an aging population demands further research into new therapies and interventions that can help us age healthily – this will not only improve the quality of life for older individuals, but also reduce the pressure on healthcare systems and the burden on society.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966880/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10188329/
[3] https://www.mdpi.com/1422-0067/22/1/401
