The Life Extension Revolution: Theories of Aging
This article is an extension of The Life Extension Revolution: Part 1. I didn’t want to include details about theories of aging in that article so I created a separate blog. I strongly suggest you start there.
Why is this (aging) even happening to you?
This question is asking about some general or fundamental nature of aging — what is aging and why does it happen? Why has aging — a characteristic that seems so detrimental to an organism — been maintained in natural selection? Aging has posed an evolutionary paradox: if natural selection leads to organisms that are optimal for survival and reproductive success, then why or how could evolution favor a process that increases mortality and decreases reproductive capacity? How could genes that cause aging evolve? Does aging have an evolutionary advantage? Evolutionary disadvantage?
Theories that attempt to answer why aging occurs from an evolutionary perspective are known as evolutionary theories. Below are some theories.
Focusing on the group, not the individual
Efforts to understand why we age go back for centuries. Early attempts suggested that both aging and death are beneficial for humans because they gave new organisms a chance to play and test which variants are more suited for survival and reproduction, i.e. they make room for the next generation. In other words, sacrifice the individual for the greater good.
In 1889, the German biologist August Weismann suggested that natural selection would favor species survival and hence aging and death were programmed — in order to make space and free resources for younger and fitter individuals. This theory doesn’t identify a mechanism for aging — it gives the purpose of aging, but doesn’t explain how individuals age.
Many early explanations revolved around group selection and survival of the species. This view was held by biologists until some time in the 20th century.
It was later argued, in the 40s and 50s, that long-lived individuals could leave more offspring than short-lived individuals so the cost of death of an individual exceeds the benefit to the group. This meant aging most likely did not evolve for the “good of the species”.
Weismann later abandoned his theory.
New theories said that since it didn’t make sense for natural selection to favor aging and death, aging must have evolved because natural selection becomes “inefficient at maintaining function (and fitness) at old age”.
Mutation accumulation (MA) theory
In 1952, Peter Medawar proposed a theory as an alternative for Weismann’s programmed death theory. He said that aging is a by-product of accumulation of detrimental mutations over time.
Medawar’s argument was as follows:
Nature is a competitive environment. Hence most organisms die or get killed before they become old and suffer symptoms of aging.
Thus, most organisms have a very small likelihood of a) being alive and b) reproducing at a later age.
Therefore, there is no strong reason why an organism would need to remain fit for long term, especially past reproduction.
This means that any detrimental mutations that happen in late life would not be weeded out by natural selection — there’s no reason to since the organism cannot reproduce so it cannot pass down this mutation — it will not effect the fitness of future generations. (Contrast this with mutations that might occur before reproduction — the organism would pass down this mutation and if it is detrimental, then natural selection would most likely weed it out.)
Senescence, then, is just the summation of such detrimental genes that are only present in older individuals. These genes accumulate over time and cause the deterioration and damage that characterizes aging.
An observation: MA does not suppose any fundamental cause of aging. In this theory aging is the result of detrimental mutations. Therefore, if these mutations could be removed or fixed, longevity may be extended.
The idea that mutations end up causing adverse effects has been verified and accepted by scientists trying to understand human genetic diseases: “many human diseases have been traced to errors that have occurred in genetic code.”
However, the current view is that MA is too simplistic and has some problems:
MA assumes that aging has a negligible adverse effect on evolutionary fitness and that’s why aging wasn’t weeded out. In other words, because absence of aging has only a small (and hence negligible) beneficial effect on fitness, evolution wouldn’t select for it.
And he assumes aging has a negligible effect on fitness of an organism because most organisms don’t live until old age (and hence don’t die from old age). The problem is that some organisms do. Aging (in mammals) affects speed, strength, and agility — and these affect fitness even in organisms that aren’t “old”, but just getting older. For example, for species that have relatively few predators and therefore live in a relatively peaceful world (e.g. elephants), old age and death end up being fitness factors. It doesn’t make sense for these to be ignored then, as suggested by Medawar. These issues led to the development of the antagonistic pleiotropy (AP) theory (below).
For example, there are signs of aging that develop in “parallel and independently” in different parts of an organ (such as age spots) — this cannot be a result of DNA mutations because how could the same type of DNA change occur in cells in different parts of an organ?
Antagonistic pleiotropy (AP) theory
Williams criticized Medawar’s assumption that the adverse effect of aging on evolutionary fitness was negligible. He said, “No one would consider a man in his thirties senile, yet, according to athletic records and life tables, senescence is rampant during this decade. Surely this part of the human life-cycle concerns natural selection. … It is inconceivable in modern evolutionary theory that senescence, such as operates in man between the ages of thirty and forty is selectively irrelevant.”
In 1957, he proposed the antagonistic pleiotropy(AP) theory as an evolutionary explanation for senescence — it said that aging was caused by the many pleiotropic genes, where each had a beneficial effect during an organism’s youth but had a detrimental effect during older age.
His argument was:
Definition: Pleiotropy is the idea that one gene can have an effect on not only one trait, but multiple traits.These pleiotropic effects affect an individual’s fitness in opposite (and hence antagonistic) ways.
AP theory says that there are genes in the body that give us fitness and fertility in youth, and those same genes become detrimental later in life, ultimately destroying the body.
But why would such genes survive then? If success in evolution means producing the most offspring the fastest, then evolution would select for that even at the cost of aging, deterioration, and death later on. These genes were maintained because of their benefits at a young age — which was an advantage, despite their negative effects (such as aging) in post-reproductive age.
Williams said that “natural selection may be said to be biased in favor of youth over old age whenever a conflict of interests arises”. It doesn’t matter what happens to the individual once they’ve satisfied the purpose of reproduction (the faster the better).
Observation: According to this theory, aging turned out to be detrimental side effect of selection for survival and reproduction during youth and becauseaging was a side effect of these necessary functions, he reasoned that intervening in the aging process would be impossible.
Current view: AP is the prevailing theory today for why (in evolution) aging occurs, but it’s not fully well-supported. On one hand, biologists have found many genes that do enhance fertility in the young (or carry some other benefits early in life) and are associated with aging later in life. But on the other hand, they have found many other aging genes that have no benefit associated with them in early life (or at least none that have been identified).
In any case, the idea that genetic trade-offs may be the cause of aging is prevalent today.
Disposable soma theory
In 1977, a statistician (now biologist) named Thomas Kirkwood published the disposable soma theory of aging — this theory is a particular case of the antagonistic pleiotropy (AP) theory. It says that organisms have a limited amount of energy which needs to be distributed among growth, reproduction, and DNA maintenance / repair. And organisms age due to this trade-off.
With finite resources, the body makes a greater investment in growth and reproduction, hence compromising the energy allocated to maintenance and repair, and this causes the body to gradually deteriorate with age.
Observation: This theory is similar to AP theory because both suggest that aging is a result of trade-offs. The difference, however, is that this theory is concerned with higher level processes and not genes.
This theory did not specify cellular mechanisms to which an organism shifts its energy — this makes is less useful when trying to understand aging mechanisms.This theory does have some inconsistencies with the observed effects of caloric restriction — experiments since 1930s have shown that caloric restriction is correlated with increased lifespan.
This theory would say that when food (energy) is scarce, then the body compromises and lowers the priority of repair and maintenance — hence the body would deteriorate. But the opposite is found — caloric restriction extends life span. One explanation is that when food is scarce, an organism can extend life span and delay reproduction until scarcity is over.
This theory also doesn’t explain why women tend to live longer than men — even though women invest far more resources into reproduction, so wouldn’t the body focus even less on repair in women than men? One suggestion is that even though women invest more energy in reproduction during fertile years, women also go through menopause — their reproduction time is limited, and this is not the case for men. So may be this restriction allows women to live longer.
So, what’s missing?
Some of the things that evolutionary theories of aging don’t necessarily explain:
There are some organisms that die suddenly following reproduction (e.g. salmon, octopus, etc.). And sudden death seems to be an example of programmed death (and not a result of gradual aging that is characterized by the side-effect or trade-off explanations.
Scientists have found that manipulating some genes seem to delay aging while not affecting reproduction — this also contradicts the evolutionary theory of aging.
These theories don’t explain animals like ants, which have a single reproductive female — their existence provides evidence against trade-offs between longevity and reproduction.
Evolutionary theories seem to imply all organisms age so they don’t explain organisms that appear not to age (earlier list).
There are animals (Painted turtles) where older females (compared to younger females) had increased reproductive output and offspring quality while maintaining survivorship.
Apoptosis, which is programmed cell death is responsible for killing cancerous cells, infected cells, and other cells that are problematic during development. Now, this is beneficial (but a problem is it seems to increase later in life) so it hints that senescence may have arisen because of an evolutionary advantage, and not because of some side effects.
In conclusion, evolutionary theories provided a theoretical framework that explained many observations, but 1) they don’t offer a complete picture and 2) they don’t offer a mechanistic picture of aging — how do we age?
The good news is that we don’t (yet) need to know the complete evolutionary“why” to try to push back aging and age-related diseases. And that’s because we know a lot about the “how”, the mechanisms of aging and they tell us how to intervene — that’s the next section.
Let’s talk about some theories of aging.
These theories say that we are designed to age and die — both aging and death are genetically predetermined and programmed — and the body follows a biological timeline. “Programmed” does not mean evolutionarily programmed; it only means that aging is predetermined by set of instructions.
This “programming” may be controlled via different clocks: molecular, genetic, neurological or hormonal or through the hypothalamus.
Gene theory: Genes program aging from birth to death. There are biological genetic clocks that switch “on” and “off” (act through hormones) to control everything: puberty, menopause, aging and rate of aging, and death. So aging and longevity are programmed. (An example is Hayflick limit: a normal human fetal cell will divide between 50–70 times before experiencing senescence — it will not divide past this point.)
Telomere theory: This is an extension of the Hayflick limit. Telomeres are specialized DNA sequences at the end of chromosomes and they serve as a protective cap. They shorten at each cell division and when telomeres become too short, the cells senesce and die, i.e. cells stop dividing. The idea is that the length of telomeres acts as a “molecular clock”.
“In white blood cells, the length of telomeres ranges from 8,000 base pairs in newborns to 3,000 base pairs in adults and as low as 1,500 in elderly people. (An entire chromosome has about 150 million base pairs.) Each time it divides, an average cell loses 30 to 200 base pairs from the ends of its telomeres”. (Source)
Shorter telomeres are found in a) atherosclerosis, b) heart disease, c) hepatitis, d) cirrhosis, etc.
When a cell divides, its DNA splits into two strands. One strand has a gap at the end — that end gets shorter after each division, until the cell can’t divide anymore. This failure in replication leads to deficiencies in cell replacement and tissue/organ renewal.
An enzyme called telomerase fills this gap. And as long as cells have enough telomerase, they keep the telomeres long(er). The problem is that with time, telomerase levels decrease and when telomerase levels decrease, telomeres become shorter.
What this means: It may be possible to slow aging by reversing the shortening of telomeres — by activating telomerase. The idea is that this would extend the Hayflick limit and hence extend human life. Currently, people are working on doing this via 3 different categories of approaches: drugs, gene therapy, metabolic suppression (hibernation).
The thing is, in aging cause and effect can be mixed up — even though telomere shortening has been linked to the aging process, it is not known whether shorter telomeres are just an effect of aging like gray hair or actually cause (or contribute to) aging.
Another interesting observation is that about 80% to 90% of cancer cells have been found to possess telomerase. So (the hope is), if telomerase actually makes cancer cells immortal, may be it could prevent normal cells from aging. May be we could extend lifespan by preserving or restoring the length of telomeres with telomerase? But if we did this, would it increase our risk of getting cancer? No one is quite sure yet.
Hormone theory: The body’s endocrine system acts as a hormonal clock, controlling hormones that regulate growth, metabolism, and reproduction. It controls the production of growth hormones and at as we age, it triggers a reduction in the production of these hormones, leading to changes such as menopause and the collection of such changes cause aging.
One problem is that this theory suggests reduced production of hormones might be a cause of aging — this led people to believe that hormones (or growth hormones) could be effective as an anti-aging strategy. But research on a variety of organisms (fruit flies, nematodes, and mice, etc.) shows that a reduction in Growth hormone (GH) /Insulin-like Growth Factor 1 (IGF-1) signaling pathway results in increased life span. So adding growth hormone to the body may produce the opposite of the desired anti-aging effects.
In the 1990s, it was shown that mutations in DAF-2 (DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in C. elegans) double the lifespan of the worms. Studies in laboratory rodents also suggest that low IGF-1 and GH levels beneficially affect longevity.
Another problem is that despite the impact of IGF1-like on C. elegans longevity and other animals longevity, its application to human aging is not as clear — there doesn’t seem to be any consistent evidence for human aging. Reducing IGF-1 has inconsistent effects on age-related diseases in humans, reducing the risks for some but increasing them for others.
Side note: Several theories suggest general imbalance as we age. Our immune system, brain, and endocrine glands (control hormones) all gradually fail over time, leaving us more susceptible to infections and diseases as well as aging and death.
Immune theory: This theory says that as we age, our immune systems become less effective — leading to an increase in autoimmune response and hence body produces more antibodies that attack itself. An example is decreased T cells (helper cells) in adults. There are increased diseases in older adults and increased autoimmune diseases in adults.
Scientists have shown that immune system functionality does decrease with age, leading to increased health risks posed by infections and diseases. The problem is (once again) that cause and effect are hard to decouple here. These changes in the immune system in the elderly could be an effect of aging, but this theory suggests aging is caused by these changes.
All of the above theories focused on programmed components — all follow some biological timetable, regulated by genes or hormones or immune system, and control processes responsible for growth, metabolism, reproduction, maintenance and repair.
Next, damage-related theories.
These theories say that aging results from an ongoing process of damage accumulation, where damage is both by-products of metabolism as well as environmental assault on the body.
This process of damage accumulation is ongoing throughout your entire life and eventually causes aging.
Let’s look at some of these theories.
Wear-and-tear theory: This theory says that changes associated with aging are the result of general damage that accumulates over time. Cells, tissues, organs, etc. wear out with ongoing use and then stop functioning. An example is the wearing out of the skeletal system — in osteoarthritis.
It’s similar to what we observe happens to nonliving things around us — components of an old car break down due to ongoing and repeated use.
The question you want to ask now is what, then, causes the wear and tear damage that leads to aging? Here are some examples (some of which are explained later):
Exposure to radiation, toxins, and ultraviolet light can damage your genes.
When your body metabolizes oxygen, free radicals are produced and these can cause damage to your cells and tissues.T
here are cells that aren’t replaced throughout your life, such as nerve cells of the brain — when these cells are lost, it eventually results in loss of functionality.
When cells divide, DNA can sustain damage and errors accumulate. In the telomere theory, we saw that just the act of cell division shortens telomere length, which eventually means the cell can no longer divide.
Oxidative damage (due to free radicals) in cells results in cross-linking of proteins — this prevents proteins from doing their jobs.
Rates of living theory: This theory says that the faster an organism uses oxygen, the shorter it lives. The idea is that each organism (or even each cell) has a specific amount of metabolic energy available and that the rate at which the organism uses this energy determines the animal’s length of life.
There are some organisms that have faster oxygen metabolisms than others and die younger. But there really isn’t much evidence for this because what we don’t know is if something (say lower temperature) slows down metabolism, then what other systems that something changes so even if organisms live longer, we don’t know why they lived longer.
Cross-linking theory: This theory says over time “cross-linked proteins” accumulate and damage cells and tissues, slowing down body processes, thus resulting in aging. For example, in the presence of oxygen, glucose binds to protein — the protein becomes impaired and cannot function properly. This causes a variety of problems: 1) when this accumulation of cross links occur in tissues (arteries, cartilages, muscles), tissue elasticity declines, 2) cross-links also do not allow DNA to take part in cell divisions, hence preventing cell renewal and 3) repair enzymes of the cell can not break these cross-links.
For example, diabetics have 2–3 times the numbers of cross-linked proteins when compared to their healthy individuals.
Free radical theory: This theory says that free radicals cause damage to cells and organs and they eventually stop functioning. (The term free radical is used for any molecule that has a free electron — this property makes it react with healthy molecules in a destructive way. A free radical tries to steal an electron from a neighboring molecule (electrons like to be in pairs) and when it steals an electron, it damages that molecule, making it a free radical).
Free radicals are a by-product of normal cell function — they bind to other essential proteins and molecules in the body, thus interfering with their function.
The free radical theory says that many of the changes discussed above are caused by free radicals. Damage to DNA, protein cross-linking and other negative changes have been attributed to free radicals. Free radicals can damage fats, proteins and DNA. If DNA is attacked, you may get a mutation that could cause aging or cancer.
The good news is that our body does have a defense system against free radicals and this defense system does prevent most damage that could occur from free radicals. According to this theory, the body prevents most of the damage, not all. And this small amount of damage accumulates over time, deteriorating our body.
Here’s the hard part: not all free radicals cause damage. So eliminating deterioration is not as simple as trying to eliminate all free radicals in the body.
DNA damage theory: This theory says that accumulation of DNA damage is a major contributor to aging (and believed to be a contributor to cancer as well).
A few things to understand:
Let’s differentiate between damage and mutation — both are types of error that occur in DNA. DNA damage is any physical abnormality in the DNA — such as single or double breaks or some other abnormality in the chemical structure in DNA. This type of damage can mostly be detected and repaired if the DNA is available for copying. As you can imagine, if the cell is non-replicating then this damage cannot be repaired. In any case, this damage accumulates over time and may block replication and the cell may die. Mutation is a change in the sequence of standard base pairs. A mutation generally cannot be recognized and thus cannot be repaired. A mutation is replicated when the cell replicates.
DNA damage, that is structure change in the DNA, can be mitochondrialDNA damage or nuclear DNA damage. Both can contribute to aging, but this particular theory talks about nuclear DNA damage (mitochondrial DNA damage is below). Nuclear DNA damage contributes to aging either directly — as listed above — or indirectly, by increasing apoptosis or cellular senescence.
Note we said that DNA damage is identified and repaired during replication (if replication isn’t impaired, which happens over time). This means that for cells that are non-dividing (or infrequently dividing), these un-repaired damages will accumulate over time. And in frequently dividing cells, when DNA damages don’t get the chance to block replication and kill the cell, they will cause further replication errors and eventually cause mutations.
It is therefore suggested that DNA damages in frequently dividing cells, (by giving rise to mutations) are a likely prominent cause of cancer. And DNA damages in non-dividing or infrequently dividing cells are likely a prominent cause of aging.
Side note 1: Cells in the brain, skeletal muscle, and cardiac muscle are examples of non-dividing or infrequently dividing cells.
Side note 2: The human genome contains about 3 billion base pairs of DNA. DNA damage occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day. They accumulate with age and result in increased incidence of diseases.
The idea that DNA damage may be the primary cause of aging is widely accepted today.
Mitochondrial DNA damage theory: This theory is close to the role of free radicals in aging. Earlier we saw that free radicals play a significant role in aging and this theory says that mitochondria is the main target of radical damage. This theory says that damage to mitochondrial DNA accumulates over time, thus impairing mitochondrial function (energy production) and producing damaging metabolic by-products. And these cause cellular damage.
Earlier we said that the cell’s nucleus has a set of defense and repair mechanisms for repairing nuclear DNA — mitochondrial DNA has no such mechanisms. Another problem is that mitochondrial DNA is close to free radical producing sites, which results in high levels of mitochondrial DNA damage compared to nuclear DNA. And this damage increases with age. Analysis of skeletal muscle from a 90-year-old man showed that only 5% of his mitochondrial DNA was full length, while a five-year-old boy’s mitochondrial DNA was almost completely intact.
It is now generally believed that the “accumulation of cellular damage” is the general cause of aging.
A quick way to think about aging:
A breakthrough paper in 2013 outlined Hallmarks of Aging — it defined aging as 9 distinct categories (hallmarks) and explained how these processes interact with each other. The paper discusses aging through the lens of damage theory.
I’ll try to briefly talk about these hallmarks — more in Part 3, when I talk about approaches.
1 — Genomic instability: There has to be a balance between DNA damage and repair systems. Over time, there is less repair and more damage, hence damage accumulates.
As noted earlier, the human genome contains about 3 billion base pairs of DNA. DNA damage occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day. Normally, our bodies have processes to repair this DNA damage or errors. And as we age, our DNA repair systems become less efficient. Ongoing and excessive DNA damage (or insufficient DNA repair) accumulates over our lives, causing aging and mutations, resulting in increased incidence of diseases such as cancer.
Note that both nuclear DNA and mitochondrial DNA are subjected to damage. Some consequences: cancer, progeric diseases, which result in rapid aging and shortened lifespan — Hutchinson-Gilford progeria syndrome (HGPS) is an example — sufferers only live until their early 20s and develop many aging diseases: atherosclerosis, stiff joints, hair loss, wrinkles, and more.
Approach to solve this problem: The idea is to restore the body’s DNA repair mechanisms. It was discovered that boosting levels of NAD helps maintain DNA repair in mice. In a recent interview, Dr. Sinclair tells how nicotinamide mononucleotide (NMN) helps repair DNA and rejuvenates mice by boosting NAD levels. A major accomplishment is that researchers are now conducting clinical trials of NMN.
2 — Telomere Attrition: This is the telomere shortening issue discussed earlier.
Telomeres are specialized DNA sequences at the end of chromosomes and they maintain the stability of chromosomes. When telomeres shorten, our DNA becomes vulnerable to degradation. Shorter telomeres cause genomic instability and may contribute to developing cancer.
Telomeres shorten over time and an enzyme called telomerase keeps telomeres longer. We saw that they decline over time and this telomerase deficiency in humans is associated with premature development of diseases.
Approach to solve this problem: As we saw earlier, our cells use telomerase to rebuild shortened telomeres. Geroscientists are looking at ways to lengthen our telomere. Using RNA therapy to lengthen telomeres, it is possible to extend the lifespan of human cells in culture. Using telomerase gene therapy allowed scientists to reverse aspects of aging and increased the lifespan of mice and the idea is to take telomerase gene therapy to FDA for human trials.
3 — Epigenetic alterations: The epigenome is a set of chemical compounds that tell the genome what to do. Think of it as the program that controls your genetic code. This program makes changes to the genome and modifies the DNA, controlling which genes to turn on or off, depending on what is required. For example, “if a cell should develop into a liver cell, epigenetic modifications will ensure that the parts of the genome specific to liver cells are expressed, while the parts specific to other cell types are ignored.”
As we age, our cells are attacked by toxins and other environmental factors. And as cells are exposed to such environmental factors, they are subject to changes in their genome via epigenetic mechanisms. Such changes accumulate over time and are correlated with the decline observed in aging cells.
Geroscientists believe these changes in the epigenome are not permanent, and theoretically, they can be reversed — they believe this hallmark can be targeted using drugs.
Approach to solve this problem: Geroscientists believe epigenetic changes in the epigenome are not permanent, and theoretically, they can be reversed. Geroscientists have found they can reset epigenetic markers of some cells so they are functionally younger again. They hope to develop drugs and processes that can reverse epigenetically-driven diseases and maybe the aging process itself.
4 — Loss of proteostasis: Proteins regulate almost everything in our body. Everything depends on proteins folding properly (think of it as a tool that needs to be assembled correctly (structurally)). These proteins face constant assaults from free radicals, toxins and other factors — and as we age, after decades of damage, proteins in our cells become damaged or unfolded or improperly folded. Our bodies have a housekeeping system (autophagy) that remove damaged or unfolded or improperly folded proteins and restore properly folded proteins. Like other things we discussed, in younger cells, this system works well. But as we age, this cleaning service degrades and becomes less efficient — our bodies can’t get rid of cellular toxic waste and cells collect junk. For example, Amyloid proteins are an example of such accumulation — they play a big role in neurological conditions such as Huntington’s, Alzheimer’s, and Parkinson’s disease.
Genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis are known as the primary hallmarks of aging — they are the foundational causes of cellular damage.
The next 3 hallmarks: deregulated nutrient-sensing, mitochondrial dysfunction, and cellular senescence are response hallmarks — they are a result of the primary hallmarks. The idea is if the primary hallmarks can be stopped, then (in theory) these response hallmarks will be reduced.
Approach to solve this problem: Maintaining protein quality control is essential to health, and geroscientists are looking at a number of potential approaches, including increasing DNA repair, genome repair, rapamycin, and drugs to regulate proteostasis. See approaches here.
5 — Deregulated nutrient-sensing: Our bodies have several different “nutrient sensing” pathways — they make sure our bodies are taking in the right amount of nutrients — not too much, not too little. If we take in too much, our cells and tissues react by storing energy and growing, if we take in too little, the nutrient scarcity activates certain repair mechanisms. As we age, these nutrient sensing pathways become damaged and cells begin to fail to recognize and respond to normal cellular signals or functions.
Approach to solve this problem: At a high level, there are four key protein groups (IGF-1, mTOR, sirtuins, and AMPK) involved in nutrient sensing that might be contributors to aging. Suppressing or turning down the pathways of the first two, IGF-1 and mTOR, promotes longevity. And turning up the pathways of the last two, sirtuins and AMPK, helps longevity. (Side note: One approach on lifespan.io: “The klotho protein is named after one of the Greek Fates. This mythological figure was said to create and control the thread of life and decided when gods and mortals would die. The klotho protein was first discovered in 1997 by a research team in Japan, which also discovered the inhibitory effect that klotho has against some aspects of the aging process….Later studies found that mice engineered to produce more klotho lived longer, which was also confirmed in humans; people who produce more klotho tend to live longer than those who produce less.”)
6 — Mitochondrial Dysfunction: Mitochondria are energy factories in our cells. And free radicals are a natural byproduct of this energy production process. Over time, these free radicals build up in our cells — they damage and degrade mitochondria.
Damaged mitochondria affect cell and tissue functions, lead to an increase in apoptosis, and produce even more free radicals — which further damage the mitochondria. The impact of mitochondrial damage is most noticeable in systems that demand high energy, such as the heart or the brain.
Approach to solve this problem: A number of approaches are being taken for preventing this. One approach is to copy the most vital parts of the mitochondrial DNA to another part of the cell — the nucleus — giving mitochondrial DNA access to better DNA repair mechanisms and hence improving resistance to damage caused by free radicals.
7 — Cellular senescence: As we age, our cells lose their ability to divide — they experience DNA damage and telomere shortening (as explained above) and they become senescent. Senescent cells cannot divide or support systems of which they are a part. When we’re young, our immune systems remove these senescent cells from our bodies, but as we age, they are not cleared and end up damaging our bodies. Accumulation of senescent cells cause a lot of problems: cells don’t divide and grow (old cells are not replaced with new cells), they don’t support or repair tissues, they damage nearby cells and tissues, they increase chronic inflammation, and eventually increase the risk of cancer and other age-related diseases.
Approach to solve this problem: Geroscientists work on developing compounds, called senolytics, which kill and clear senescent cells from the body. When given to mice, these compounds rejuvenated old mice, making them look like younger mice. Several of these compounds are scheduled for clinical trials.
8 — Stem cell exhaustion: All cells in your body have the same genetic code but different parts of DNA are turned on or off in different cells. Most cells cannot change the settings that tell what to turn on and off, i.e. liver cells will not have the same settings as lung cells. But stem cells have a lot more flexibility — they can turn into pretty much any type of cell in the body. As our tissues and bodies are damaged, stem cells replenish and repair them. And when we are young, we have enough stem cells to do this well. But as we age, stem cells (like other cells) are affected by accumulation of damage and lose their ability to divide, resulting in a decline in stem cells. As a result, we start seeing signs of aging. In other words, aging is not only about the increase of damage, but also about the failure of our bodies to repair this damage (and hence accumulation of damage), and this is fundamentally connected to the decline in stem cells.
Approach to solve this problem: Stem cell research has made rapid progress in the last decade or so. There are already various stem cell therapies in clinical use, in clinical trials (or scheduled for clinical trials). Some of them try to repair stem cell damage, some try to replace existing stem cell components, and others try to fight stem cell senescence.
9 — Altered intercellular communication: In order for our bodies to function normally, our cells must constantly communicate with other cells — they must transfer information to each other and one example of such communication is via hormones. As we age, communication between cells deteriorates, i.e. not just the signals sent by cells, but the ability of other cells to receive this information also deteriorates. This dysfunctional communication leads to issues such as chronic inflammation and unhealthy hormonal changes, which can lead to increased incidence to infections and diseases.
Approach to solve this problem: As cells age, they produce inflammatory distress signals that damage surrounding tissues. Inflammaging is chronic inflammation that comes with aging and hence is persistent. This leads to damage, dysfunction, and disease. Geroscientists are working on a variety of approaches to to dampen inflammaging and to regulate a wide range of hormones, proteins, and pathways (such as Wnt signaling pathway and (mTOR) pathway).
These 9 hallmarks are determined mainly by genetics, but are affected by environmental factors. And all of them contribute to damage and over time our bodies can’t repair this damage, which eventually leads to aging, age-related diseases, and death — The Self-Destruction Countdown and then The Ultimate Cliff.
Aubrey de Grey and SENS
A massive figure in the field of rejuvenation is Aubrey de Grey — he’s a world famous gerontologist. But more importantly, he’s been fighting this fight for a few decades — before most people cared about it and before people wanted to put money in this field.
When Aubrey’s mother died, she left him with $16 million. He could’ve done anything with the money, but he dedicated $13 million to attack and eradicate aging. He thinks this is one of the biggest problems facing humanity and he’s been working relentlessly to fight it.
He describes aging as follows: Metabolism causes damage and damage eventually causes pathology. He says, “Metabolism (the hugely messy network of homeostatic processes that keep us alive) causes pathology (the hugely messy network of anti-homeostatic processes that kill us).”
Therefore, his approach to solving aging is via maintenance and repair. He uses the analogy of a 50- year-old car that still runs well due to exceptional maintenance to make his point. This maintenance approach, he says, should extend the human life span if we keep damage at manageable levels throughout the human body.
He categorized damage as the following Seven Deadly Things:
Cell loss, cell atrophy — cells dying so too few cells
Division-obsessed cells — too many cells
Intracellular junk — junk inside cells
Extracellular junk — junk outside cells
Extracellular matrix stiffening — protein crosslinks
He claims that there is no new type of damage — these 7 types summarize the types of damage that cause aging.
Aubrey de Grey believes rejuvenation via maintenance is the idle approach — not the other two traditional approaches.
For each damage type, his organization — SENS — has suggested an approach to attack it (more on this in Part 3).
Over decades, many attempts have been made to understand aging and researchers have made tremendous progress. The good news is that recent research suggests that there may be a limited number of these mechanisms, giving scientists hope that it may be possible to develop approaches and strategies that could help humans live longer and healthier lives.
For us laypeople, here’s how we can think about the problems.
And here’s how we can think about the solutions.