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Role of ‘Junk DNA’ in Aging and Age-Related Disorders

Dr. Francis Crick, one of the discoverers of the DNA structure, proposed a central dogma in 1958 which became imperative in genetics and molecular biology. He described the central dogma as genetic information from the DNA gets converted into messenger RNA or mRNA (transcription) which then gets converted into a functional protein (translation). In 1972, a geneticist named Susumu Ohno described all the non-coding sequences in the genome as “junk DNA” i.e. the part of the genome that does not form an mRNA and thus does not form a protein.

Almost 50% of the junk DNA consists of repeated sequences that are randomly scattered throughout the genome of the organism. These repeated sequences may have originated from viral elements called transposons. These transposons have inserted themselves into our genomes and transposed (moved) themselves to different sections of the genome before being silenced. Most of these regions contain multiple copies of the transposon as they copy or cut themselves from one part of the genome and reinsert themselves into another part. 

Not much research had been done to decipher the role of this junk DNA in the human body.  However, in the last decade, considerable research has shown that some of this genetic material does have a function, mainly in regulating the expression of various genes in the host. Scientists were able to prove that the junk DNA was involved in generating different RNA molecules that helped to regulate protein production. 

Small interfering RNAs (siRNAs), microRNAs (miRNAs), small nuclear RNAs (snRNAs), long noncoding RNAs, etc are produced by the non-coding DNA region. They are of varying lengths and structures with some even folding upon themselves to form a hairpin loop. These molecules can selectively bind to a particular target mRNA to either inhibit or promote protein formation. 

Aging or senescence is a natural process that occurs due to the aging of the individual cells as they undergo cell division and DNA replication. Each of the DNA strands in a cell is capped with telomeres which guard the chromosomes and shorten with each cellular division. This forms the basis of aging. As the telomeres shorten beyond a limit, the DNA replication does not occur properly leading to aging and subsequent death of the cell.

The telomerase gene regulates the expression of the telomerase enzyme which forms new telomeres after replication and restores the length of the telomeres. In a healthy organism, higher telomerase activity is restricted to the gonadal cells, although it is also expressed at a higher level in cancer cells. 

In a 2021 study, researchers from the University of Washington identified a VNTR2-1 sequence that drove the activity of the telomerase gene, which was previously proven to prevent aging in certain cell types. The study also identified that VNTR2-1 sequence length varies in the genomes of Caucasian and African-American individuals. The researchers also observed increased telomere activity in individuals who possessed a longer sequence of VNTR2-1. 

In a paper published in the journal Aging, researchers discovered that such repeat sequences become active with time as the organism ages despite being inactive during the early years. This could be due to the disruption of the DNA-histone protein complex, (chromatin) which enabled the expression of the repetitive sequences. 

Scientists from the Garrison Institute of Aging, Texas detected microRNAs in blood and serum using quantitative RT-PCR, microarray, and sequencing techniques. They observed that these miRNAs serve as peripheral biomarkers of aging and age-related diseases such as dementia, cataract, osteoporosis, diabetes, hypertension, and various neurodegenerative diseases

Long noncoding RNAs, which are only found in primates, have been speculated to regulate aging via chromatin modulation and telomere maintenance. Their levels are inconsistent with age and also in various age-related diseases and may play a role in aggravating such disorders. Scientists have found out that some long noncoding RNAs influence the expression of certain tumor suppressor genes with age, thus playing a role in the regulation of lifespan.

Although more work has to be done to identify all the biomarkers and more components of aging, there is hope that in the next 20 years, a solution for aging in an individual can be obtained based on the levels of the noncoding RNAs in their circulating blood.

Author:

Jervis Fernandes is currently pursuing a Ph.D. degree in biology at IISER Trivandrum and is interested in all matters of RNAs in cell signaling, hormones, development, and lifespan.

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