When I had serious coronary problems in December, 2016 and nearly died, the personal implications of aging in humans became very real. The general question of why we humans get older and eventually die, and of whether we can do anything about it, was the main reason I studied biology for my PhD.
One of my favorite books of all time is “Aging, Sex, and DNA Repair” by Carol and Harris Bernstein (please carefully note the comma between “Aging” and “Sex”). This brilliant review of the biology of aging is a little dated, but still excellent reading.
My research life took a different path (neural development in C. elegans and then genetic engineering of bacteria), but I’ve maintained a keen interest in all things “aging” as I succumb to the inevitable process myself.
There’s some fascinating new research out that deepens our understanding of the basic epigenetic, gene-regulatory mechanisms that may underlie fundamental aging mechanisms. Before we talk about that (near the end of this article), let’s do a quick review of some of the most popular scientific views of why and how we age just so we’re all on the same page.
Some observations on aging and death
Biologists (and philosophers before them) have been intrigued with aging and death for a long time. Do all organisms have a set number of years or days before they die? Why and how does an organism grow old (senesce) and die? Does aging and death give an organism a particular evolutionary advantage?
Different kinds of organisms (whether plant or animal) have characteristic life spans. Humans live to around 90-110 years under the best possible conditions, but mice only live about 2 years. Elephants live on average about 50 years, but their normal maximum lifespan is about 75 years. Some larger birds (parrots, cockatoos, vultures, albatrosses) also live to a maximum of around 75 years. See here for an interesting discussion of some long-lived organisms.
In general, bigger animals live longer
The graph below shows, the general relationship between body size (mass) and lifespan (longevity on a log scale). The longer-lived species are closer to the top of the graph and the bigger ones are to the right. In general, bigger animals live longer than smaller ones, with a number of notable exceptions.
The animal silhouettes represent a selection of species with much longer or shorter life spans than expected given their body size. These species are (A) Brandt’s bat; (B) naked mole rat; (C) Andean condor; (D) African elephant; (E) emu; (F) Papuan forest-wallaby; (G) pied kingfisher and (H) forest shrew.The relationship between longevity and size is a little different for flying animals than for non-flying. So, blue points and line represent flying birds and mammals. Red points and line represent non-flying birds and mammals.
To some extent, larger animals have slower metabolisms than smaller ones. It’s an easy conclusion that slower metabolism (lower oxygen consumption) might lead to longer life spans. Recent research supports this idea somewhat but not perfectly.
Humans and other primates live much longer than similar-sized mammals (click here to read). Herman Pontzer, an anthropologist at Hunter College in New York and lead author of one study, explains, “Humans, chimpanzees, baboons, and other primates expend only half the calories we’d expect for a mammal.”
However, other studies suggest that other factors may be at play. Increasing caloric consumption in mice by almost half (by raising them in cold temperatures), has no noticeable effect on their lifespan.
A large study of 1,456 mammals, birds, amphibians, and reptiles showed that, after correcting for body mass and phylogeny, basal metabolic rate does not correlate with longevity in mammals or birds. However, the age at sexual maturity is typically proportional to adult life span. Mammals that live longer for their body size, such as bats and primates, also tend to have a longer developmental time for their body size.
What are the main theories of why we age?
There are a few competing basic theories and ideas around the phenomenon that all multi-cellular organisms undergo. They tend to fall into two camps: the “breakdown” camp and the “biological program” camp.
Within these camps, a number of competing hypotheses have been proposed over the centuries (most coming in the last 50 years as the molecular basis of biology was revealed). Here’s a sampling:
Hormones are master regulators of human development, so it’s reasonable to think that they may influence life span as well as other stages of human development. As we age, we go through a variety of hormonal changes leading to adolescence, maturity, and senescence.
The hormonal changes that accompany menopause in women are among the most obvious of these changes, but testosterone levels tend to fall in older men as well. Growth hormone, aldosterone (adrenal steroid), dehydroepiandrosterone (DHEA), and insulin levels also tend to decrease as we age.
Of course, it’s still an open question what drives changes in hormone levels at various stages of human development.
“Rust” theories (oxidation of metabolism)
The dominant forms of life on Earth all use oxygen to metabolize sugars. But it wasn’t always this way. About 2.3-2.4 Billion years ago (at least 1 Billion years after life first appeared on Earth) cyanobacteria—oxygen-producing, photosynthetic organisms—first appeared and changed the planet’s atmosphere. Prior to that, oxygen was a toxin, rare and poisonous to most organisms.
Our metabolism has changed over the eons, but deep in the core of our cells, within our basic metabolism, oxygen is still a reactive toxin to many basic biochemical processes. In its ROS – Reactive Oxygen Species – radical form (superoxide O2–, peroxide H2O2, or excited singlet oxygen 1O2), it reacts vigorously to damage proteins, fats, DNA, and structural carbohydrates.
ROSs are produced by the mitochondria inside our cells. These organelles link metabolism of sugars to oxygen uptake and CO2 production. Like all biochemical reactions, mitochondrial oxygen in the so-called Electron Transport Chain is not perfect. Occasionally (more often than we’d like), oxygen doesn’t get properly consumed in chemical reactions, but produces some kind of ROS.
ROS theories of aging are thought to be overly simplistic these days, though they were popular from the 1950s through the 1980s. The correlation between the rate of metabolism (use of oxygen) and the speed of aging is not perfect.
Still (and remember this for later), the only reliable way we currently know to reduce aging in mammals is to drastically slow metabolism by reducing caloric intake.
Some of the most compelling evidence that there may be a “genetic clock” to aging came from a very strange source, the compost-dwelling, microscopic nematode C. elegans.
This worm has a normal maximum lifespan of about three weeks under optimal conditions. But, environmental factors, like an absence of ready food, can cause juvenile worms to develop into an alternative, long-lived form, beginning about a day after hatching. This so-called “dauer” stage can prolong the worm’s life four-to-eight times beyond the normal.
The suggestion that this genetic program might affect aging in general came when Cynthia Kenyon’s lab found a mutation in the dauer progam genes that lived twice as long as normal, though it never formed the dauer stage. Subsequent studies showed the genes involved all played a role in hormonal regulation, through Insulin-like Growth Factor 1 (IGF-1).
But what could be the origin of such a genetic factor, and how might it be regulated?
The well-known Hayflick limit, first described in the early 1960s, showed that human cells can only divide about 40-60 times before they become genetically unstable and division stops. This was quickly shown to be due to shortening of telomere segments at the ends of chromosomes.
Human DNA (and that of all plants and animals) comes in the form of a double-chained helix. The simple DNA molecule wraps around proteins called histones and coils in tight bundle into chromosomes. Each chromosome contains at least two DNA double helices.
It has long been known (since the 1980s) that when the DNA of a cell replicates, the sequences at the very ends of the DNA (the telomeres) are not completely reproduced. They get a little shorter each time the cell divides. The telomeres are simple repetitive sequences that don’t code for any proteins so this is harmless at first. But after the telomeres shorten enough, the protein encoding regions begin to be affected and the cell is no longer capable of dividing.
In cancer cells, a protein enzyme called telomerase, repairs the shortened ends of telomeres, making these cells capable of replicating indefinitely; they become, essentially, immortal. Many people still think telomeres are a good candidate for expressing the aging program, but others point to contradictory evidence.
Recent research is now pointing to a new candidate.
The Epigenetic Program
Parts (about 2% in humans) of the long DNA double helix encode proteins; the rest is regulatory regions or spacers, often called “junk DNA.”
Proteins are the actual metabolic workhorse of the cell. Proteins perform the biochemical reactions of metabolism; they organize the components of cellular structure; they coordinate cellular communication and patterning.
Turning the production of a certain protein on or off can have a dramatic effect on the cell. Cells regulate the expression levels of proteins very carefully using several different mechanisms. In order to produce a protein, the encoding DNA must be transcribed into RNA and the RNA is then translated into protein. Controlling which proteins get produced, where and when, is the job of the gene regulatory mechanisms.
While much gene regulation is encoded by parts of the nearby DNA (e.g. so-called promoter and enhancer regions), there is another kind of regulation that doesn’t depend on the specific sequence of the regulatory regions.
Epigenetics is more about inheritable gene regulation than simple inheritance of the gene per se, the normal study of genetics.
“Epigenetics is the study of heritable, reversible forms of gene regulation that are not dependent on the DNA sequence. This regulation includes DNA methylation and histone methylation, acetylation, ubiquitination, and phosphorylation. Recent studies have shown that epigenetics plays a central role in many types of diseases, including cardiovascular diseases, neurological diseases, metabolic disorders, and cancer.” See original article.
Some epigenetic regulation can be inherited for many generations, making it look like its own kind of gene. But what is inherited is the methylation state of DNA, for example, rather than the gene sequence itself. This affects whether the gene is expressed or not, rather than whether it (i.e. a specific allele or version) is present. Like other kinds of gene expression, epigenetic information encoded by DNA methylation is tightly regulated.
What’s the latest on epigenetic regulation of aging?
Recently, Shinji Maegawa and colleagues at Temple University in Philadelphia showed that epigenetic information encoded by DNA methylation changes over time in an age-specific way.
As mice, monkeys, and humans age, some regulatory sites go from high methylation to low, while others go from low to high. This is called “epigenetic drift” and the rate of change is highly characteristic in each of these three species. The graph below shows the rate of epigenetic drift is lower in longer-lived humans compared to monkeys and mice).
“Our study shows that epigenetic drift, which is characterized by gains and losses in DNA methylation in the genome over time, occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans,” said Jean-Pierre Issa, MD, Director of the Fels Institute for Cancer Research at LKSOM, and senior investigator on the study. This might explain why mice live only about two to three years on average, while rhesus monkeys live about 25 years, and humans 70 or 80 years.
The rate of epigenetic drift is conserved in a species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans.
Great! What can we do about our epigenetic state?
When mice and monkeys in the study were put on highly calorie-restricted diets (30 to 40% less than normal), their DNA methylation states more closely resembled younger animals and the rate of epigenetic drift slowed. Caloric restriction had no effect on telomere shortening in older mice or monkeys. The same rate of telomere shortening with age was observed whether animals had a normal or restricted diet.
Perhaps epigenetic drift is the long-sought after genetic clock. It is certainly a good candidate though we don’t yet completely understand how DNA methylation is regulated. A number of drugs can affect(even reverse) DNA methylation, including DNA methylation inhibiting drugs, bromodomain inhibitors, histone acetyl transferase inhibitors, histone deacetylase inhibitors, protein methyltransferase inhibitors, and histone methylation inhibitors. Some of these drugs are being explored for treatment of age-related diseases such as cancer. None have yet been tested for general anti-aging properties.
But if epigenetic changes in DNA methylation is truly the main aging clock, and if these changes can be affected by the same life-extending caloric restriction that is known to extend life spans, maybe anti-aging drugs aren’t that far away.
Now all we have to do is figure out how to develop a pension plan for a society where more than half its members are retired. What do you think? If you could live a healthy life for many hundreds of years, would you? How would a huge population of “young senior citizens” affect our society? Share your thoughts in the comments section below.
And thanks for reading – Paul