“Jumping Genes” Reduce Lifespan?
Transposable Elements and Lifespan Reduction
Survival of the fittest.
The backbone of the Darwinian theory of evolution that we are all familiar with. If a trait makes a certain animal more likely to survive (among other often smaller factors), then that animal will have a higher reproduction rate, leading to more animals in the next generation possessing the advantageous trait. As this cycle continues, the trait eventually becomes common across all members of the species.
However, for a species to truly evolve, it must continuously be developing newer traits, which, if helpful for the organism, will be preserved. And these new traits arise from random mutations in one’s genome. These mutations can be caused by a range of factors, like DNA damage caused by the environment (ex. UV radiation), or mistakes made during DNA replication that go unnoticed. These mutations, if they occur in the coding region of the DNA, can cause changes in the structure, or building blocks, of various proteins. These changes often have no effect, but they can also be damaging or advantageous to the organism. If they’re damaging, the species is less likely to reproduce, and the mutation is unlikely to be passed on and preserved. If the mutation creates an advantage, however, like making a giraffe’s neck longer, then it is likely to be passed on and preserved.
However, with the increased understanding of genetics, and the advent of genomics, scientists have begun to notice that the same mutations that might be extremely valuable to push evolution forward might be extremely harmful when it comes to living a long, healthy lifespan.
And one factor responsible for evolution that shows this lifespan-reducing impact most clearly is the LINE-1 “jumping gene”.
Genes That… Jump?
“Jumping genes”, or more scientifically, transposable elements (TEs), are genes that can move, or “jump”, around the genome. They are found in virtually every organism, including bacteria, and make up a large part of the genome. In fact, 50% of the human genome is estimated to be made up of TEs. The exact mechanism through which these TEs move around the genome depends on the type. The two main types of TEs are retrotransposons and DNA transposons.
Retrotransposons move around the genome by first being transcribed into RNA molecules, which are then converted back to DNA, by reverse transcriptase enzymes, and inserted at a different location in the genome. There are two types of retrotransposons: LTR retrotransposons that possess long terminal repeats (LTRs), or long sequences of repeating nucleotides near the end of the gene, and non-LTR retrotransposons. Two important examples of non-LTR retrotransposons are the Alu and LINE-1 transposons, which are currently the only two active TEs in the human genome.
DNA transposons are characterized by terminal inverted repeats on both ends. These repeats are simply inverted compliments of one another, and play a role in being recognized by the enzyme transposase, the enzyme that allows the TE to replicate and move. All forms of TEs also contain flanking direct repeats, which play a role in the insertion of the TE, and are left behind as “footprints”.
But what role do transposons play?
Well, when it comes to their function… there essentially is none. From a strictly theoretical point of view, TEs are essentially just selfish genes that want to be replicated as much as possible. But looking at it experimentally, TEs have loads of effects. One of these is their ability to cause genomic instability at a local level, involving mainly mutagenesis upon insertion, and DNA double-stranded breaks. The TEs can insert themselves at virtually any location in the genome (given that a few requirements are met of course), including in the middle of other genes. This can cause mutations to take place in protein-coding or regulatory regions of the genome, which might be harmful, advantageous, or silent. Furthermore, certain proteins associated with LINE-1 (L1), known as L1 ORF2 proteins, can also induce double-stranded breaks into the genome even without L1 transposition. Cellular repair of these double-stranded breaks often induces more mutations into the genome.
Due to these mechanisms, TEs are exceptionally impactful on the process of evolution, serving as a constant source of genomic innovation. But, the same processes that are so useful for the evolution of species might serve to reduce the length of an individual’s life.
Non-LTR Transposable Elements and Human Longevity
As you might expect, overexpression of TEs can induce numerous damaging mutations that may contribute to cell death and degeneration of function in a variety of tissues and organs. As one gets older, the mutations slowly accumulate in the cells, causing more and more loss of function. In fact, activation of TEs has been associated with the onset of cellular senescence, a major hallmark of ageing.
To combat this, cells evolved mechanisms to suppress TE transcription with epigenetic changes. Essentially, the cell adds markers to the sites where these TEs are located, preventing transcription from taking place. These could be methyl tags added to the gene itself, or removing acetyl groups from the histone proteins, causing the DNA to wrap around the histones more tightly and restricting access to the machinery responsible for the transcription process. Such regions of the DNA where genes are prevented from being transcribed are called heterochromatin, while regions where genes can be expressed are called euchromatin. Some researchers have also linked proteins called sirtuins, which regulate histone acetylation and have been strongly linked to human longevity, to the regulation of TE transcription.
However, these epigenetic systems slowly break down as one ages, due to accumulation of what is called epigenetic noise, causing genes within traditionally heterochromatin regions to be activated, while other genes in euchromatin regions are repressed. And with this decline in heterochromatin integrity, cells also show increased expression of TEs, contributing to the degeneration of the integrity of the genome. This causes regulatory proteins like sirtuins to be distracted as they rush to sites of DNA damage to prevent the expression of mutated genes, leaving behind unregulated regions of heterochromatin that begins to be expressed and continues the cycle of epigenetic noise.
And so, with the breakdown in epigenetic mechanisms, TE expression is not only increased with age, but also contributes to the molecular and cellular mechanisms responsible for ageing. But, there are some ways that their impact can be reduced, slowing the progression of ageing and extending the lifespan significantly.
How To Prevent It?
Scientists have found several ways of preventing the action of TEs, some involving therapeutics that have effects at the molecular level, while others involve lifestyle changes.
One of the safest and easiest of these is dietary or caloric restriction. Dietary restriction has been repeatedly found to make a large impact on slowing ageing and has even been observed to reverse epigenetic age. As the name implies, this practice involves controlling the amount and kind of food we consume. Dietary restriction has been observed to oppose an age-related decrease in heterochromatin integrity, by activating several pathways involved in maintaining the epigenome during cellular stress. As such, in tissue models, TE expression had the most significant increase when given high-calorie food, while dietary restriction caused a lower increase, or even decreased the expression of TEs with age, 87% lower relative to high-calorie foods. Furthermore, dietary restriction also delayed transposition until later in life, allowing for animal models to live a much healthier and longer life compared to high-calorie models. But, other than reducing the amount of food you eat and controlling what you eat, what else can be done to prevent transposition and the resulting progression of ageing?
Another highly impactful approach to inhibiting TE transposition was increasing the expression of two systems responsible for maintaining the heterochromatin in cells: the siRNA (small interfering RNA) pathway, involved in transposon silencing, and Sir2, a type of sirtuin. Scientists found that this approach overwhelmingly attenuated expression of TEs following these genetic interventions, suggesting that activation of these pathways prevents the age-related loss of TE silencing and heterochromatin integrity. But unfortunately, this approach is far from being safe to use in humans, due to the high unpredictability and ethical issues with genome engineering in humans. So, until gene editing becomes safe enough to be used in humans, you’ll just have to stick to watching what you eat.
Now preventing TE expression doesn’t prevent ageing entirely. Watching what you eat won’t make you immortal. But it will fix/prevent a ton of problems in your body commonly associated with age, allowing you to live a healthier and longer life. And until we finally figure out what causes ageing, that’s the best we can do.
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On A More Personal Note:
I am a 17-year old currently obsessed with the science behind aging, and if we could live forever (because, let’s be honest, no one wants to die).
I do have more articles coming up, including one on coronavirus vaccine research right now, so be sure to follow me here on Medium, and check out some of my older articles while you’re here.
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