Life is short.
With every passing minute, with every breath you take, you unknowingly get closer to death. You celebrate by adding more candles to your birthday cake every year until your youthful exuberance gives way to the subtle signs of aging, at which point your age is no longer an appropriate question to ask. Your mirror begins to reflect a face that’s slightly less familiar, with deepening wrinkles and declining energy levels, until your bodily functions are shutting down to the point that you find yourself outstretched on your death bed. It isn’t until that moment that one typically realizes this universal truth and wishes they could change it.
Life is short, but what if it doesn’t have to be?
Take some of the medical conditions that claim so many lives every year, like heart disease, cancer, or Alzheimer’s disease. They are all worsened by a common factor: aging.
Aging is a disease, one of the leading causes of death, yet we simply accept it as an inevitable part of life. In the past century alone, we have been able to double our lifespans. Instead of resigning ourselves to a lifespan of roughly 80 years, we can begin to understand the complexities behind aging to find the Elixir of Life that scientists like David Sinclair, Laura Deming, and even Voldemort had been searching for to not only double that number, but also improve the quality of those added years — increasing your healthspan- to avoid the fate of the Greek legend Tithonus.
Types of Age
When asked to verify your age at a liquor store, the answer you give is the number of years since the D.O.B on your license, or the number of years you’ve been alive. These rotations around the sun reflect your chronological age, which put simply, is the number of candles on your birthday cake.
However, in terms of aging, your chronological age doesn’t tell the whole story when predicting your life span — it is your biological age that takes the cake. It refers to the condition of your body and its functions or processes based on certain biomarkers that can determine how healthy you are and how much time you have left to live by revealing the amount of damage that has occurred. For example, smoking accelerates your biological aging due to the harm it causes, making your body older than what it actually is.
To turn back every tick of our biological clock, we must address the comprehensive list of nine identified hallmarks of aging that explain why we age.
We’ll break down a few of the primary hallmarks step by step and delve into the possibilities of mitigating them throughout this article. However, to have a deeper grasp on the process of aging, we must understand one of the key biomarkers that dictate our lifespan—epigenetic alterations.
Epigenetics🧬
As you may have learned in your high school biology class, every cell in your body has the same DNA. This tongue-twisting double-stranded helix structure makes up the genome of living organisms with the 4 A, C, T, and G nucleotide bases.
However, a brain cell has a different function than a skin cell, but how can they be distinguished if they have the same DNA? Different cell types have different epigenomes, which allows each cell to know which processes to carry out. Each of the approximately 200 cell types in your body has the same genome but its own distinct epigenome.
Genes in DNA sequences are expressed when they’re read and transcribed into mRNA, which is translated into proteins by ribosomes in a cell. These proteins determine the characteristics and functions of the cell. The prevention of the transcription of DNA into RNA disrupts protein synthesis and gene expression, which allows for cellular differentiation and is done primarily in 3 different ways.
- DNA Methylation
Small molecules known as methyl groups, which are binded to its cytosines in specific places on the sequence, are highlighted using chemical signaling markers. The methylation of the labelled region prevents the proteins which would otherwise attach to DNA from “reading” the gene, effectively inhibiting the mRNA transcription and expression of that gene by turning it “off”. Think of methylation like a yellow highlighter instructing a skin cell to skip over and not read the highlighted information of how to be a brain cell. Methylation of the wrong genes can contribute to aging.
(Fact: The Horvath Clock is a biological aging clock that can estimate a person’s biological age based on changes in their DNA Methylation patterns!)
2. Histone Modifications
DNA is wrapped around proteins called histones at varying levels of tightness depending on the chemical groups at the tails. When histones are tightly packed together, the polymerase cannot access the DNA due to sirtuins or deacetylases, so the information in the chromatin is not transcribed and the gene is turned “off”. When histones are loosely packaged, or acetyl groups are attached to them, the exposed DNA can now be transcribed, turning parts of the sequence back “on”. Cells place acetyl groups on histones near relevant genes for their function, so heart cells have acetylated histones near heart cell genes, and brain cells have acetylated histones near brain cell genes.
(Fact: DNA Methyltransferase Inhibitors (DNMTis) or Histone Deacetylase Inhibitors (HDACis) can be used for non-permanent epigenetic editing!)
3. Non-coding RNA
Non-coding RNA, such as miRNA, helps to control gene expression by attaching to the coding RNA that is required for genes to be “read”, such as mRNA. When miRNA binds to mRNA, it interferes and blocks its transcription process so that it cannot be utilized to produce proteins, turning genes “off” while also finding the specific proteins that will modify histones to become tighter and stop genes from being expressed.
Epigenetic Alternations
As you age, you lose information in your epigenome. These epigenetic alterations that define cell identity are altered, leading to issues in cell function. They don’t change your DNA, but they change which genes are expressed, and there is speculation behind whether or not these changes are hereditary.
Your epigenetics are also influenced by environmental factors and experiences. On bright summer days when you go out to tan in the sun, the chromosomes of your skin cells break due to heavy UV radiation. The effort that it takes for the cells to stick the chromosome back together by unwrapping the DNA, recruiting proteins to help, and resetting the structure, takes time and is not completely efficient. Overtime, histones are not returned to the correct state and DNA methylation is added in the wrong places. As this damage accumulates, gene expression patterns are affected, leading to genomic instability. The complete resetting of the epigenome happens about 99% of the time, but that 1% contributes to the aging process.
It is known that with aging, the body’s ability to maintain homeostasis (remain stable regardless of the changes in internal and external cell conditions) decreases. The tendency of the genome to undergo alterations in DNA information content through mutations is considered a hallmark of aging. Spontaneous mutations result from errors in natural biological processes, while induced mutations are due to agents in the environment that cause changes in DNA structure. Even a difference of one nucleotide can be enough to cause significant problems in the body.
(Fact: Sickle Cell Anemia occurs because of a difference in a SINGLE nucleotide in the gene that codes for a subunit of hemoglobin of a carrier's DNA compared to a non-carrier’s DNA.)
David Sinclair, an acclaimed professor of genetics researching the biology of aging at Harvard Medical School, has claimed that it is epigenetic alterations that are accelerating aging. If we can reverse epigenetic alterations and the other hallmarks, we can reverse aging.
Telomere Attrition
Telomeres are often compared to the plastic caps on the end of shoelaces, called aglets, as they both act as protective measures, but for our chromosomes. The polymerase enzyme, telomerase, allows these repeats of the nucleotide sequence to act as helmets on both ends of your chromosomes to safeguard the DNA within. Every time our cells undergo mitosis and meiosis to make copies of DNA packed into chromosomes, where it divides and multiplies to form new cells, the telomere caps get shorter, compromising the integrity of the DNA.
After a certain number of replications, the telomeres shrink to the point where the DNA is no longer protected. Cells are usually able to replicate 50 times, reaching the Hayflick limit, before the telomeres practically disappear. Your body recognizes when this takes place and triggers a DNA damage response (DDR) in the cell, sending it into cellular senescence.
(Fact: The length of one’s telomeres can be used as a predictor of biological age!)
Senescent Cells
Senescent cells are somatic cells that are dormant in the body. When cells become senescent, they underproduce a protein that tells them to die. To resist cell death, senescent cells activate pro-survival and inhibit pro-apoptotic pathways. Without the ability to multiply, they still can perform regular metabolic functions to produce energy for the cell and prevent DNA mutations. Senescence is primarily caused by these 3 factors:
- Replicative senescence — when a cell has hit the threshold for maximum number of cell divisions.
- Stress-induced senescence — when oxidative stress causes breaks in DNA and triggers a DDR.
- Oncogene-induced senescence — when oncogenes, genes responsible for cell replication, are over-expressed.
To prevent damaged cells from proliferating in the body and forming tumors, the cell activates the two tumor suppressant pathways. This alerts the immune system by secreting pro-inflammatory cytokines, produced from a SASP phenotype. Cellular signaling encourages chronic inflammation and cellular senescence in other surrounding cells, causing them to accumulate in the body and age faster. For example, they can damage skin cells to cause wrinkles, or they can degrade cognitive functions if accumulated in the brain.
(Fact: Turritopsis Dohrnii, otherwise known as the Immortal Moon Jellyfish, is a species known to lack senescence and essentially age backwards, reversing DNA damage and returning to a polyp! )
How can we stop this?
Well, senescence can be avoided by maintaining telomere length during cell replication by using telomerase. However, this state of senescence, which inhibits replication, serves as a crucial barrier against the formation of cancerous tumours. While through replicative senescence, the chances of yielding a cancer cell are 1 in 10,000,000, telomerase overexpression elevates this probability to 1 in every 3 cells, leading to uncontrolled proliferation.
When telomerase is overexpressed, the cell must induce a DNA Damage Response (DDR) through alternative means, such as oxidative stress, in order to enter senescence. During this prolonged period, the cell racks up significantly more genetic mutations from DNA damage. Thus, tumor-suppressing genes, such as the p-53 gene, are more likely to be inactivated.
Thankfully, there are therapies in development that do not promote cancer! We’ll examine some current pathways below as well as studies performed primarily on mice with promising longevity results!
Senolytics
Senolytics are a class of drugs that selectively eliminate senescent cells from the body. Senolytics target senescent cells and either upregulate their pro-apoptotic pathways or deregulate anti-apoptotic pathways, effectively killing them and reversing the aging process. Scientists have discovered a peptide that eliminates senescent cells without damaging healthy cells.
In late 2016, Mayo Clinic injected proteins dasatinib and quercetin, two senolytics, in a group of mice. It increased their lifespan by almost 35%, and was able to kill a whopping 80% of all their senescent cells while causing almost no harm to healthy cells, with some regrowing lost hair!
Early human trials have begun, treating patients with lung disease to improve their walking distance within a six-minute timed period by 21.5 meters, a feat considered impossible with current lung disease therapies.
Sirtuins
Sirtuins, a group of proteins with diverse functions, including transcription regulation, apoptosis, inflammation control, stress resistance, and energy efficiency, are a promising anti-aging strategy. These proteins, encoded by the SIRT genes, rely on the concentration of NAD+ in an organism, which we will explore later.
In humans, the sirtuin family consists of seven members (SIRT1–7), each with distinct localizations. Sirtuins 1, 6, and 7 are found in the nucleus, sirtuins 3–5 reside in mitochondria, and sirtuin 2 is present in the cytoplasm.
Multiple studies have proven that sirtuins play a key role in cellular responses to oxidative stress and are crucial for cell metabolism, as they maintain their structural integrity and thus their function. Sirtuins exert significant control over the stability of nearly all cellular proteins through two primary mechanisms: Deacetylation, which regulates protein production, and ADP-ribosylation, which alters the structure and activity of proteins. If we are able to further activate sirtuins in our body, then we can help ourselves live longer. How can we achieve this?
NAD+
“NAD+ is the closest we’ve gotten to a fountain of youth. It’s one of the most important molecules for life to exist, and without it, you’re dead in 30 seconds.” — David Sinclair
Sirtuins consume a redox co-enzyme called NAD+ (Nicotinamide Adenine Dinucleotide)- a “helper molecule”- to stimulate sirtuin activity but also for us to maintain robust mitochondrial function. The decrease in energy levels as we age can be attributed to the waning efficiency of these cell powerhouses. NAD+ plays a part in turning nutrients into energy, by transferring electrons to help synthesize ATP.
Our bodies constantly need to make NAD+ to survive, but this is significantly degraded overtime in our bodies by the enzyme CD38. This is why fewer sirtuins are created as we age, and is one of the reasons why we become more susceptible to diseases. Low amounts of the molecule are linked to skin cancer, Alzheimer’s, cardiovascular disease, as well as multiple sclerosis among others. A key approach to counteracting sirtuin decline is to boost their activity by replenishing NAD+ levels.
NAD+ Precursors — NR and NMN
NAD cannot directly enter cells, as there is no specific transport protein for it. Our body can only synthesize NAD+ from five different precursors: Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN), Nicotinic Acid (NA), Nicotinamide (Nam), and Tryptophan (Trp).
Four out of five of these are forms of vitamin B3, and of the five, NR and NMN are the most efficient. Numerous clinical studies have demonstrated that through a process called the salvage pathway, supplements of NR or NMN can be converted in the body to increase NAD+ levels in humans. These supplements can be introduced in the body through pills or intravenous administration.
NAD+ has been tested on mice by David Sinclair and his team at Harvard Medical School. After putting drops of NAD+ into the drinking water of the mice, in only a few hours, the NAD+ levels in the mice‘s bodies had risen significantly. The tissues of a 2-year-old mouse and a 4-month-old one were indistinguishable.
In another experiment, mice they gave NMN to ran so far that the treadmill stopped working, as the program was not designed for mice that were able to run more than three kilometers. Three kilometers for an old mouse when most of us can’t even do that today? That’s like a 80-year-old running a marathon faster than a 20-year-old. Gone are the days where you’ll need to exercise to keep your blood pumping; NMN can even reactivate faltering blood flow to all organ tissue.
Couldn’t NAD+ precursors be used as anti-aging pills?
You wouldn’t be the first to think so. Companies have already been researching the field and developing FDA-approved supplements to slow down aging. Companies like Elysium Health and ChromaDex have made daily NR supplements, with their respective Basis and Niagen pills to increase NAD+, and Elysium’s research has demonstrated that Basis can boost levels by an average of 40%, as shown in a 2017 human study. Others are using NMN, such as Alive by Science and Thorne, to do the same in combination with other drugs to activate sirtuins to slow aging processes.
Rapamycin to inhibit mTORC1
Some types of newly discovered anti-aging drugs attempt to block aging pathways. Mammalian Target of Rapamycin (MTOR), is a protein kinase that plays a vital role in cellular processes such as growth and survival. While it has certain benefits, excessive mTOR signaling has been associated with uncontrolled cell proliferation, linking it to carcinogenesis. MTOR is an attractive target for drug development because of its role in various diseases, including cancer, diabetes, and neurological disorders.
It also negatively affects autophagy, the process by which old cells in the body are broken down to avoid senescence and maintain efficient body operations. Ideally, this process should operate as consistently as possible, which can be done by deregulating mTOR. Rapamycin does exactly that.
To understand how rapamycin acts as a selective mTOR inhibitor, it’s crucial to recognize that mTOR exists in two distinct complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). These complexes differ in composition, regulation, and downstream effects. mTORC1, activated by amino acids, nutrients, energy status, and growth factors, governs cell growth, protein synthesis, and autophagy. On the other hand, mTORC2, activated by growth factors, oversees cell survival, metabolism, and cytoskeletal organization.
Despite the significance of both complexes in promoting longevity, the drug Rapamycin specifically targets mTORC1. By doing so, it offers a means to decrease the protein while optimizing autophagy and metabolic processes for longevity. This is achieved through its interaction with FK506-binding protein 12 (FKBP12), and it has been scientifically proven that this approach effectively extends the lifespan of mice.
Researchers have investigated the effects of administering rapamycin at a later stage of the mice’s lifespan. Even with the late-stage intervention, the mice experienced an extension of lifespan and a reduction in age-related ailments, also proving its efficacy as a cancer-preventative agent.
But forget the minuscule biological details and focus on the bigger picture;
Scientists have fostered increased lifespans in living organisms using Rapamycin, so where is our spot in the line?
Far in the back, unfortunately. Rapamycin is only effective for older mice, and although extended lifespan is what we strive for, it seems a bit fruitless to do so when one’s health span has already reached its worst. Additionally, inhibition of mTOR is not optimal for us, as we still need activation of the mTOR pathway to heal wounds, grow our ever-shrinking muscles with age, and make energy for our cells to counter declining levels. This paradox of both inhibiting and activating something at the same time is difficult to work around, and when paired with the severe negative side effects of rapamycin, it’s quite a challenge to work through.
Regardless of its drawbacks, there have still been numerous studies utilizing Rapamycin as well as other anti-aging drugs and compounds to slow down the process of aging that have shown promising results.
But what if you wanted to take it a step further? Instead of simply delaying the rate at which we age, why don’t we reverse aging altogether?
Reversing Aging
In 2012, Japanese scientist Shinya Yamanaka won the Nobel Prize for his discovery of what is now known as the Yamanaka Factors. The Yamanaka Factors are 4 genes that control transcription (transfer of DNA info to mRNA) in your body. What Yamanaka did was insert the four genes, through viral gene therapy (inserting the gene through a virus), into adult cells. The Yamanaka factors essentially wiped off all of the methylation in the cell, turning it back into a stem cell.
(Fact: You can literally scrape a skin cell off your arm and reprogram it into a brain cell. You can even take a skin cell from an old mouse and clonally turn it into a newborn mouse with just the use of four types of proteins. Insane!)
Stem Cells
Stem cells are the original cells that can transform into any other specialized cell in the body, and produce exact copies of itself for growth and repair.
Embryonic stem cells originate in the earliest stages of life, from the zygote formed through the fertilization of sperm and egg. As the zygote divides and replicates at an exponential rate, a group of 16 cells, known as the morula, forms quickly. The subsequent development of a morula into a sphere-shaped blastocyst unveils two key components: the trophoblast and the inner cell mass (ICM). Within the ICM, we can find embryonic stem cells (ESCs), characterized by pluripotency — the ability to develop into any cell type in the human body.
ESC’s can also replicate indefinitely, which makes them beneficial for regenerating lost cells through the existence of degenerative diseases, but is also useful for tissue or organ transplants and even drug discoveries.
However, while ESCs have the potential to be successful in terms of longevity, an ethical dilemma arises from the fact that obtaining ESCs typically involves the destruction of human embryos. The considerations surrounding their acquisition have led to scrutiny and the exploration of alternative approaches.
(Fact: Instead of using stem cells taken from embryos, many researchers are looking into stem cells from the placenta, which is both convenient and ethical after the baby is already born — check out more information here!)
One alternative pathway is the development of induced pluripotent stem cells (iPS cells). iPS cells share similar characteristics with ESCs, but are generated by reprogramming adult cells. They hold promise in changing, or rather, extending our lives for the better.
The key to extending our lifespans could be within these answers, and who knows, you might be the first in your family to live up to 200 years old.
I guess that begs the question; if you could extend your lifespan, how long would you want to live for? I’ll let you reflect on that.
TL;DR
- Longevity is the concept of extending people’s healthspan and lifespan.
- Epigenetics is the expression of your DNA, and contributes to aging. One’s genetics, environment, and lifestyle all play a part.
- The nine hallmarks of aging are the factors that contribute to the aging process. If we can reverse these, we can reverse aging.
- Certain methods to combat the aging process, such as senolytics and stem cells, are already being tested. However, many of them aren’t quite the solution we need.
Congratulations on making it this far! Thank you so much for taking the time to read this rather lengthy article about how to add more candles on your birthday cake. I hope you were able to learn something new, and gain a deeper understanding of the complexities within our bodies.
By no means am I an expert on aging, or any sort of biology in general, but I write solely to express my passions and interest in the field and regurgitate my learning for others. I hope you enjoyed — until next time!
Hi, my name is Arya and I’m a 16-year-old longevity enthusiast! If you liked this article, give it a clap and drop a comment! Follow for more related articles :)
