Why do we age?

Everyone knows that different species can have dramatically different lifespans. Mayflies can have a lifespan as short as few hours. A tree colony called Pando in Utah’s Fishlake National Forest is believed to be the oldest living organism on Earth with estimated age of 80,000 years, though it is perhaps even as old as 1 million years. The oldest known human being was a French woman, Jeanne Calment (1875–1997), who lived to be 122. The maximum lifespan of a given species, along with its particular aging process, is believed to be rooted in genetics. With the introduction of technologies that allow for the decoding of entire human genomes, it is no surprise that anti-aging research is currently exploding.

With such variations observed, aging is still a mysterious process from a biological point of view, as to why it even occurs, and if it is a built-in evolutionary process. The underlying biological mechanisms that cause aging remain largely unknown. This obviously is a huge impediment to the development of the desired pharmaceutical interventions to slow the process of aging, and old age continues to remain one of the strongest fears we face throughout our lives.

First of all, what is aging anyway? It is the progressive decline of your body functions due to accumulated damage, which at the same time increases the likelihood of developing chronic diseases. This occurs because, as we age, we have a continuous reduction of available stem cells (which can be transformed to any new cell type needed in the body), that could replace those damaged cells, eventually leading to a build-up of unrepaired cells.

Why does aging exist? Modern evolutionary theories of aging, propose that evolution does not necessarily select against aging because it mostly occurs past the reproductive age, so any accumulation of mutations in the DNA that lead to aging are irrelevant to inheritance. Alternatively, different inherited mutations might have a different impact at different stages of life, so some mutations might be good from a reproductive point-of-view in earlier life stages but not be beneficial later in life. However, this concept might be quite limiting in order to explain the variations observed in aging even just among people, let alone the variety of species.

The most recent theory is termed “selfish anti-aging”, which proposes that there could be an evolutionary selection for genes that enhance longevity past the reproductive stage into the “parental care” stage which would “increased the chance that parents survive through the development of their offspring.” Somewhat oddly, the author termed these putative genes “i-genes”, suggesting that i-genes might not have been yet uncovered because the majority of aging research is performed using model organisms of far shorter life-spans where the parental care stage is not as significant as those for humans, other primates, or whales.

For whatever evolutionary reasons, aging appears to be genetically conserved. From a programmed DNA perspective, aging occurs due to specific genes. You can remove certain genes from organisms and extend their lifespan. Aging is also a function of how these genes are used, which itself could be influenced by environmental factors (through epigenetic regulation, which involves placing chemical information on top of your DNA or alternatively on top of the molecular complexes responsible for using DNA). This area of research is especially attractive to those interested in reversing aging. And finally, cellular lifespan is also regulated through influencing the length of telomeres. Telomeres are structures at the end of chromosomes (tightly packaged DNA where human genome DNA is compacted into 46 chromosomes – half of which you inherited from either of your parent). Telomeres themselves are also made up of DNA, a specific code of DNA repeated many times over. Every time a cell divides, a fraction of that telomeric DNA is not duplicated, and with each cell division the telomeres shorten. Once they reach certain length, it is a signal for a cell to no longer divide (termed senescence). This process is not present in all organisms, and it can be manipulated to be reversed as well.

Epigenetic regulation of aging

Why would we need aging to exist then? Counterintuitively, an over-abundance of food requirements could be one such important trigger to speed the aging process, and that could be to regulate the population size (termed “demographic theory of aging”). Reproducing is one thing, but living too long at the expense of limited available resources could jeopardize the survival of the entire species. The reverse of that is the concept of extending lifespans due to a challenging environment, which even has a name – hormesis. The best studied and understood example of this is restricted caloric intake; underfed animals live longer! Another example of hormesis is exercise which is known to increase the average lifespan despite the exertion and damage it enacts to the body.

Gene expression does change due to aging, and if this is due to a pre-existing program of self-destruction, in theory it could be manipulated to restore the body to a youthful stage of existence. This is why epigenetic manipulation to reverse aging is such a hot topic of interest. Let us go a little bit into what is meant by “epigenetic changes”. “Epigenetic” refers to changes that do not affect the DNA code directly, but rather how it is used. This is a broad term and can include changes to certain proteins that are involved in decoding the DNA for cellular purposes, or changes encoded on top of the DNA code. Most frequently, this involves attaching a small tiny chemical structure on top of the DNA double helix at a specific DNA sequence.

DNA itself is composed of four chemicals called nucleotides which are abbreviated as A, C, G or T. The DNA sequence that is epigenetically modified is a repeated sequence of CGCGCG, termed “CpG islands”. The tiny chemical that is attached on top of those DNA CpG islands is a methyl group: one carbon atom with a few hydrogen atoms attached to it, making it truly one of the most basic building blocks of all living things. Thus the process is called “DNA methylation”. How does it affect the use of DNA? These CpG islands are often near the genes. A gene is the DNA section that acts as a blueprint to build all the proteins in your cells; you can think of proteins as miniature molecular robots that execute nearly all the work inside the cell. Heavy methylation of the CpG islands can result in shutting off the function of a specific gene; it will no longer be used as a blueprint to produce more proteins. At that point, the power is out at this miniature factory!

Thus, you can appreciate how the concerted manipulation of genetic function as we age could reduce aging effects such as increased inflammation, the reduced production of anti-oxidants, the destruction of muscle cells or nerve cells, and the reduced production of stem cells, as well as many others. In support of that are the first clinical trials for anti-aging involving a metformin drug, which has been implicated in countering many damaging effects of cellular biochemical pathways.

Also supporting this notion are the many blood parabiosis experiments – supplementing the blood of younger organisms to promote rejuvenation in older animals by gaining access to blood components present in younger individuals that are no longer expressed in older individuals. Others still argue that perhaps how the genes are used in aging is not pre-programmed self-destruction but rather could be a protective response instead. So tampering with it might in fact be more detrimental rather than protective. With manipulation of the genome function, you never know what the unintended consequences could be.

Dozens and dozens of chemicals have been found that extend the lifespan of different model organisms used for such studies. And some of those have found their way into the research of anti-aging drugs for humans, as well. Apart from the above-mentioned metformin, other best candidates include rapamycin, aspirin, and statins, as they appear to exhibit anti-inflammatory, anti-infectious, anti-carcinogenic, and cardiovascular protective mechanisms. But with these, as well as with many other candidates, we still have to sort out the long-term impact with regards to side-effects and to whom such potential anti-aging drugs can be safely prescribed, while also figuring out the reasons for the numerous conflicting results whenever any substance is being studied. So don’t expect to be popping an anti-aging pill tomorrow!

But the idea that aging could be reversed by managing the makeup of your biological factors that induce aging is certainly taking a foothold in the public consciousness. There are a lot of substances being pushed onto the public for their purported benefits with or without any scientific substantiation. As crazy as it sounds, recently the FDA had to issue a warning against the infusion of infant/child blood for the purpose of reversing aging. Clearly, whoever is doing this in order to achieve a longer lifespan probably does not understand the complexity of human blood and the intense unique viral load that each human possesses. You should never infuse yourself with someone else’s blood unless it is a medical emergency. And if people are willing to do that to counter aging, what else are they doing that might seem more innocuous?

Genetic manipulation of aging

If aging is indeed built-in into our DNA program, then without a doubt the most controversial approach to anti-aging would be to remove the program from our DNA. Is that even feasible? Not until we have a complete understanding of genome function, which at the moment still appears to be lightyears away. But if we did, in theory the DNA could be reprogrammed to prolong the human lifespan. Such an undertaking would likely require hundreds - if not thousands - of modifications within the genome if the goal is strictly to remove pre-existing programming, as the aging process could encompass numerous biological processes besides mere stem cell renewal.

One such example is a recent demonstration of the genome editing of human cell lines with the CRISPR/Cas9 system to enhance the use of a gene responsible for the production of Klotho protein. Before we get into the mystery of the Klotho protein, let us sidetrack into a bit of the CRISPR/Cas9 system background. Currently it is all the rage in the biotech and clinical worlds, obtaining enormous attention since the first successful CRISPR/Cas9 use demonstration, only few years ago. This system is a specialized defense technique of bacteria. When bacteria are invaded by viruses, they can duplicate a segment of that virus into their own genome. It is then used to produce RNA, a short single-stranded copy of the DNA that is actually the real blueprint used to produce proteins, as opposed to using DNA directly. RNA can be used by the bacterial protein Cas9 as an identifying tag to bind to an invading virus and cut it up. Can you see how it might be used for human genome editing yet? Provide the Cas9 with an RNA tag that is equivalent to any desired region in the human genome, and it will cut the DNA in that position. That’s step one. Then you need a template DNA to guide the repair at the cleaved site, and here you can introduce the desired change that will be incorporated into the repaired genome DNA. Since then CRISPR/Cas9 has undergone numerous iterations to make it more specific and streamlined for our gene editing purposes with future clinical use in mind.

Going back to the Klotho protein, it is named after the goddess who spins the thread of life because of its famed anti-aging properties. Mice that are missing this protein age faster and experience premature death, while increased levels of the Klotho protein extends the lifespan by 30% in mice. Remarkably, humans have been identified who have a mutant version of the Klotho protein, which increases cellular levels of the protein, promotes longevity, and in addition, appears to deliver neuroprotective effects resulting in enhanced cognition in these people. What is there not to like? Thus, this demonstration of how DNA could be rewritten to enhance the production level of this special protein holds great potential promise for future gene therapies, not merely to enhance the lifespan, but from a medical point of view, to help in the treatment of such conditions as Alzheimer’s disease or multiple sclerosis.

The next level of reprogramming the DNA to remove the impact of aging would be not just altering the DNA code to mimic what is already found in humans, but to introduce a completely new synthetic program that is not only not observed in humans, but potentially anywhere in nature. Of course, at this point we are talking about generating a new life form, a form of transhumanism. Could that ever happen? Unfortunately, playing with a human genome has already commenced, far more prematurely than the world could have ever expected. Only time will tell if humans will break the threshold of rewriting their own biological code to generate completely new beings, perhaps even a new humanoid species. If there were one crazy reason why this would ever be attempted, chasing immortality could very well be that spark. But at first, it will most likely be sold to the public under the auspices of medical progress.

It has certainly begun, once again, using mice.

A few years ago, a scientific study received a lot of attention when it demonstrated that the lifespan of mice could be extended by over 25% through selective targeting and the elimination of damaged cells that accumulate as a result of aging. Such treatment also reduced the age-related kidney or cardiac function impairments.

The type of cells that were targeted were cells with accumulated levels of a specific protein called p16INK4a or just p16. Another quick biology side lesson: the protein was termed p16 because this protein is 16kDa in size, or 16 kilodaltons. What is a Dalton? It is a unit of measure of atomic mass. One Dalton is equivalent to 1/12 the mass of a carbon atom. What this means is that hundreds of individual atoms make up this specific p16 structure, with a combined weight of 16,000 Daltons, or equivalent to 1,333 carbon atoms. But of course carbon is not the only atom found in proteins, although there is not much more. These atoms are arranged into specific biological entities called amino acids, which are the building blocks of proteins, typically composed of carbon, hydrogen, and nitrogen atoms, followed by oxygen, and seldomly sulphur. Place these amino acids into a long chain (based on the blueprint found in RNA code), and their electromagnetic properties allow them to interact and form complex three-dimensional structures called proteins, a major functional unit of a cell. Genes are the segments of the DNA sequence in the genome that are responsible for synthesis of proteins, and hence why so much attention is being paid to understand what the functions are of all the different genes, as most human diseases (but not all), stem from mutations found in the genes.

The p16 protein is known to increase in aging cells in all mammalian species tested so far. It is such a consistent event, that this is one of the most certain biological determinants of the aging process. Oh, and incidentally, smoking is also known to increase cellular p16 levels for those of you who are looking for yet another reason to quit smoking. The p16 protein is a blocker of regular cell proliferation, and therefore it is activated, or is called into action, during cellular events when it would make sense to pause the process before the cell divides into two, for example, due to DNA damage. Intuitively it makes sense, as you do not want cell division to proceed with damaged DNA because it could cause harm in subsequent daughter cells. What is interesting is that if this protein is around long enough, and enough of it accumulates, p16 will induce such cells to enter a process known as “cellular senescence”, where the cell is permanently arrested from further division.

It was this type of senescent cells that were being destroyed in these experimentally designed mice with longer lifespans. But it is how these mice were designed that was truly the ingenious part of the experiment, yet that has not received much attention at all. When you read this stuff, you will think it is science fiction, except it is minus the fiction, just pure clever science. So how did the authors manage to prolong the lifespan by removing senescent cells?

They did this by creating a biological construct that would be activated only in senescent cells, and furthermore, once activated, lead to their death, hence clearing the cells from the body. For this purpose, a hybrid fusion of two different genes was created that could produce a new protein composed of two specialized components. One segment of the hybrid protein consisted of a fragment of a protein called Caspase 8. Caspase 8, when bound to a second copy of itself, initiates a cellular signal that leads to a cell death event called “apoptosis”. This is basically cellular suicide. The second component of the hybrid construct was a fragment of another protein called FKBP, which can also dimerize with itself, but only in the presence of a specialized drug. Therefore the authors had a construct that they could manipulate to bind to itself with the addition of a drug at a time of their choosing and which would lead to cell death. To ensure that this construct was produced and accumulated in senescent cells only, it was placed under the same regulatory mechanism that induces the production of p16 proteins in the cells. So as p16 accumulated in aging cells, so did the foreign construct. Then you provide the drug, the construct dimerizes and poof! Gone are the aged cells!

That’s still not everything! Yet another gene was added to the construct, the encoding green fluorescent protein. It is a protein that in nature is involved in bioluminescence, producing green light when stimulated with a specific light wavelength. Therefore the expression of this protein provided easy proof that the genetic construct was successfully generated in mice, and that it was active. And that is still simplifying the process! This construct was then injected into fertilized mouse eggs and transgenic mice were allowed to age. The authors could visually confirm where in the body the senescent cells were accumulating, or show their disappearance once such cells were induced to die by injecting the mice with the drug.

If you think that this mouse model that was generated to reduce the aging process is big news, this entire system was actually devised by the authors over a decade ago already, which allowed them to specifically target the elimination of fat cells! That’s right, with the injection of a drug, they were able to produce fatless mice! Now, imagine how many people wish that they could use such a trick: pop a pill and all of your fat is gone! Ha, not so fast! In fact, this mouse model served as excellent proof that the complete elimination of fat can cause metabolic disorders or affect proper inflammatory responses, so now you can say that some fat is always good. Which it is, as fat is not some inert mass that is just stored in your body; fat is actually part of a living tissue that works along with the rest of your body. Too much of it or too little of it is not a good thing.

Have the scientists finally discovered the means to expand our lifespans? While this is a great clue, the targeting of the p16 function might not be such a simple way of cheating the aging process just yet. Inhibition of proper p16 function, not surprisingly, can lead to cell over-proliferation, such as is observed in many cancers or some congenital diseases. For example, certain mutations in the EZH2 gene, the product of which is a protein that takes part in silencing p16 production, are responsible for the Weaver syndrome that is characterized by rapid and uncontrolled growth. Pharmaceutical suppression of the EZH2 protein, on the other hand, has been shown to inhibit tumor growth in mice. Elevated p16 protein levels in cancer cells can even be predictive of therapeutic responses in specific cancer subtypes, such as enhanced positive response to radiation in prostate cancer.

This is what was meant by mentioning that modifying the human genome into completely new configurations is only a fantasy at this point, and that a full understanding of the genome function would be required in order to play God with the limits of our own species. While ingenious genome modification in mice can enrich our understanding of the biological process of aging, we still have to wait to figure out how senescent cells should best be cleared from our bodies to trick the aging process.

Healthy lifestyle, healthy lifespan

While there might not be much you can do at the moment to reverse aging, or any clinical methods that you can utilize for preventing aging, right now your best bet would most likely be utilizing diet to reduce the process of aging, as well as exercising.

Food-derived substances are another hot area of research. It is an easily appreciated concept as nutritious fresh food has been thought of as the best form of medicine for centuries. That is great when you paint the picture with such broad strokes, but what exactly in the food can promote anti-aging? Then when you do get to the bottom of that, you still need to figure out what the recommended daily allowance is of such a substance! What are the side effects? And what about the incredible variation of how such substances are provided to the consumer – how does that affect its function? Many of these substances might not even work unless delivered in concert with other compounds for a synergistic effect that is still not fully appreciated. One good example of that is the often touted beneficial impacts of anti-oxidants, which have failed to demonstrate the benefits of any anti-aging properties or of preventing disease development under experimental settings, perhaps due to the lack of accompaniment of correct synergistic partners.

Nevertheless, the potential of well-studied food chemical candidates for anti-aging effects, include resveratrol from grapes or berries, epicatechin found in chocolate, quercetin found in red onions or kale, curcumin, and L-theanine isolated from green tea. Thus, if anyone ever offers you chocolate with onions, take it!

However, if you elect to experiment on yourself with diet, would you be able to monitor your anti-aging effects? There is actually a test available that tracks the epigenetic impact on your DNA, which very accurately determines your biological aging. Biological aging does not have to correspond with your chronological aging (and an epigenetic test for that is also available), but biological aging is one of the best predictors of your remaining life expectancy. So the better your diet is in order to affect the negative impacts of gene use associated with aging, the better your biological aging outcomes will be, and you can literally track this to note your progress.

Of course we would be remiss not to mention that one of the best ways to protect your health in general is by decoding your DNA to learn how the mutations correlate with different health outcomes. That is the immediate process which you can investigate, and if any diseases or disease predispositions are uncovered, you can take mitigating steps.

But in the future it is very likely we will uncover mutations that correlate with advancing the biological aging process. This is one of the advantages of obtaining a full genome sequence: you only need to decode your DNA once with a single comprehensive DNA test (full genome). You receive an immediate interpretation at that point, but your DNA sequence is available for as many future re-interpretations as you like. And as you age, the medical and biological understanding of the DNA program will always continue to advance.

One genome DNA test in a lifetime, for a lifetime of interpretation!

If you need access to the best-quality clinical full genome DNA testing, or biological aging epigenetic DNA testing, we at Merogenomics can set you up.

So until we start tinkering with the human DNA program to circumvent the aging process, your only current method to cheat aging appears to be caloric restriction, but remember… some fat is always good!

Happy genomes and graceful aging!

This article has been produced by Merogenomics Inc. and edited by Kerri Bryant. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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