Aging has been accepted as a normal biological process that is inevitable. This deterioration of structure and function and loss of homeostasis over time is considered to some to be a collection of pathological processes or disorders that can be slowed or stopped. The search for the fountain of youth is ageless. Studies in the search for this “fountain” have begun to focus on the relationship between gene expression and the onset of age-related illnesses and conditions. Included in these research quests is the study of the human genome and identifying the factors related to aging and related conditions.
Trends and Challenges in Aging Research
The biological research arena has different focuses and areas of concentration. Studied areas include from the search and characterization of longevity genes to determining the link between life expectancy and telomere length. Also studied are the mechanisms associated with the increased risk of age-related diseases, such as Alzheimer’s disease and arthritis.
The position of the National Institute on Aging of the NIH promotes the concept of healthy aging. The institute focuses on the prevention or delay of age-related deterioration or disease. Some of the areas of focus include the role of oxidative stress and hormonal changes on the advancement of age-related decline in structure and function.
The results of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study conducted in humans show that decreasing caloric intake could have positive effects on survival and disease risk (1). Changes in some of the parameters studied (lowered triiodothyronine and metabolic rates) have been found to increase longevity in laboratory animals (2). Other studies have shown that mimicking fasting states with resveratrol may have similar effects. Studies in overweight mice treated with resveratrol showed a decrease in age-related deterioration (3).
Value of NGS in Aging Research
The search for reliable longevity and aging markers are ongoing. To date, many genes have been found to influence human longevity (4), including APOE and BRCA1. Next generation sequencing (NGS) has changed the panorama of scientific discovery and research approaches to genomics. Given the high-throughput nature and significantly lowered costs over conventional sequencing methods, enormous amounts of data are achieved in record time. This is being leveraged to approach questions regarding the existence, identification, and function of genes in longevity and factors that affect the biological aging process. The greatest challenge of the use of NGS to study aging or other areas is the crucial need for bioinformatics expertise and tools to decipher the massive data sets.
Sebastiani et al. used NGS platforms to study the genomes of centenarians and super-centenarians in an attempt to understand the genetics of those with significantly longer than average life-spans. The studies uncovered what the investigators considered to be variants (validated in larger studies) representing longevity genes (PMS2 and GABRR3) (5). Exome sequencing of the genome of certain populations (patients with Nasu-Hakola disease) has suggested a link between the bone and Alzheimer’s disease signs. Bone cysts and fractures precede this form of early-onset dementia and is linked to a homozygous mutation of the triggering receptor expressed on myeloid cells 2 (TERM2)(6).
It has been held for many years that the lifetime accumulation of somatic mutations contributes to improper proteins that affect structure and function associated with aging and shortening of lifespan. After conducting whole genome sequencing of various tissues of a 115-year-old woman, Holstege et al. concluded that the somatic mutations detected did not shorten the woman’s lifespan (7).
Currently, the large-scale gene expression study, Atlas of Gene Expression in Mouse Aging Project (AGEMAP) identifies and catalogs genes that are differentially expressed with aging in numerous mouse tissues. The use of NGS to study the transcriptome has the potential to provide additional powerful information for this effort. Next-generation sequencing using RNA-seq has the sensitivity to identify low levels of age-associated transcripts (8).
Current and Future Applications of NGS in Anti-Aging Research
The human aging process involves changes in mitochondrial structure and function. Greaves et al. analyzed human colorectal epithelial tissue from individuals ranging from 17 to 78 years of age using various methods including NGS (9). The NGS results detected mtDNA mutations in somatic cells. Interestingly, the rate of mutation did not appear to change much with increasing age, although the number of mutations did change significantly with age. The genomic data suggest that the mutations that occur early in life can expand and accumulate with age.
Next-generation sequencing is proving valuable in the search for age-related gene variants. Whole-exome and whole-genome sequencing of tissues from centenarians was conducted by Ye et al. They compared the genomes of 100-year old and 40-year old twins. However, the accumulation of somatic mutations with aging was not detected (10). Gierman et al. used NGS to sequence the genomes of 17 white female supercentenarians; however, no protein-altering variant associated with longevity was identified (11).
Human Longevity, Inc. (HLI) is a genomics-based technology company with the mission to create an extensive database of whole genome, phenotype, and clinical data. One of HLI’s goals is to find ways to effectively change the risk of disease with aging and increase human longevity accompanied with increased health. Armed with a number of Illumina HiSeq X Ten Sequencing systems, they are embarking on cataloging and analyzing samples from a variety of populations.
Although there remain challenges in the interpretation of NGS data, it is proving to be a powerful tool in helping to gain insight into the highly complex mechanisms associated with biological aging. Biological aging is characterized by higher disease risks, but it is also associated with structural changes (facial and other bone anatomy) that are yet to be linked with molecular and biochemical mechanisms. Further development and design of bioinformatics tools will bolster the interpretation and application of NGS data obtained with longevity research efforts.
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