Each hallmark is a part of a larger field of scientific inquiry, and
many are the basis of developing therapeutics to extend healthspan.
Your genome is more than a long sequence of DNA letters. DNA strands are wound around spools of protein called histones, and both DNA and histones can have various chemical handles, cranks, and levers attached to them to help turn genes on or off. These handles, cranks, and levers comprise your epigenome.
Your epigenome changes as you age — levers are lost, added inappropriately, or shifted around. As a result, precise coordination of gene activity can be compromised. The most common of these levers is something called a methyl group. The pattern of DNA “methylation” is now being used as a “biological clock,” to indicate your biological age. We know these clocks can be affected by lifestyle. The exact meaning of your biological age as measured by these clocks is still being worked out, so for now we do not recommend commercial tests of your biological age to monitor your health.
Another particularly well-studied group of molecules that influence the epigenome is the sirtuins, molecules that remove one type of epigenetic handle. Interestingly, your epigenome can be modified by diet, other lifestyle factors, and pharmaceuticals.
Evidence that the epigenome affects aging comes mostly from the study of yeast, worms, and flies. However, dietary restriction in mice slows epigenetic changes, and they show signs of accelerated aging.
The main job of genes is to make proteins, which are the heart and soul of cells’ biology. Proteins regulate virtually all chemical reactions and provide cell structure. Protein homeostasis, or proteostasis, is the maintenance of all proteins in their original form and abundance.
In order to perform their duties, proteins must be folded in precise, complex shapes like origami. However, with age proteins are damaged by normal cellular process and when damaged begin to misfold.
Misfolded proteins not only fail to perform their normal job, they can clump together, and become toxic. Alzheimer’s disease is an example of an age-related disease caused by protein misfolding.
The importance of maintaining proteostasis can be seen in the elaborate cellular systems for maintaining it: there are specialized molecular devices to repair and refold damaged proteins as well as to degrade irretrievably damaged proteins and replace them.
Several pieces of evidence highlight the role of proteostasis in aging: misfolded proteins increase with age; protein misfolding occurs in the brain and muscle of Alzheimer’s patients; both genetic and drug-induced enhancement of protein quality control will extend life in mice and such drugs are currently being studied for their impact on certain diseases such as Alzheimer’s disease.
When nutrients are abundant, animals including humans grow and reproduce--the evolutionary imperative. When nutrients are scarce, evolution has designed animals to focus on tissue maintenance and repair, for instance by stimulating the repair of damaged DNA in your cells or boosting your immune response.
Studies have inhibited the signaling of nutrient abundance by reducing food consumption, by fooling the body into thinking fewer nutrients are available with drugs such as rapamycin, and by inhibiting the signals of insulin or its close relative, insulin-like growth factor.
All of these strategies enhance health and longevity in mice and other species and appear to do many of the same things in people.
Mitochondria—often called the “powerhouses of the cell”— places where most of your cells’ energy is produced. Unfortunately mitochondria also produce most of the free radicals, or as scientists more commonly refer to them, Reactive Oxygen Species or ROS in your cells.
As ROS damage nearly any molecule they touch, for many years it was thought that ROS were the major culprit behind aging and that minimizing them would lead to longer health and life.
However, in the past decade, it was discovered that sometimes lowering ROS had no impact on health. Moreover, sometimes actually increasing ROS, by inhibiting mitochondrial function, seemed beneficial. The newer thinking is that ROS are important in signaling cellular stress.
Cells, organs, and tissues that sense stress increase their maintenance and repair processes in response to the stress. Current thinking suggests that ROS production should be in a Goldilocks zone, not too much, not too little, just the right amount.
Recent studies have found that malfunctioning mitochondria can lead to cellular senescence (see below).
Cells that once replicated vigorously but have now entered a nondividing state are called senescent cells. Senescent cells accumulate with age. Our bodies have ways to kill malfunctioning cells, but with age that ability diminishes and senescence cells are especially difficult to kill. They persist and secrete damaging molecules into the surrounding area.
Telomere attrition is one cause of cellular senescence, although other types of damage can also trigger this state. For years, it was debated whether senescent cells contributed to aging or were simply a protective mechanism against the development of cancer.
Recent work, in which mice were genetically engineered so that researchers could eliminate many of their senescent cells, has clearly shown many health benefits, including longer life. A number of drugs have been discovered that kill senescent cells but have no effect on normal cells. These drugs improve health in mice and dozens of clinical trials are now underway to see if they do the same in people.
The ability of our tissues and organs to regenerate and repair damage is critical to maintaining health. Our bodies’ ability to regenerate tissues and organs depends on healthy stem cells--the ultimate source of new cells — in virtually every tissue.
Healthy stem cells must replicate when required, but not otherwise. The replication ability of stem cells--and their ability to replicate only when needed — declines with age.
Several labs have now shown that stem cell function can be resuscitated by external factors such as the as-yet-unidentified rejuvenating factor(s) found in the blood of young mice or humans, opening the door for possible pharmacological prolongation of stem cell health.
An exciting new direction for aging research is that we have learned how to turn any type of cell into a stem cell in a laboratory dish. The hope is that these lab-induced stem cells can eventually be reintroduced into the body to enhance tissue repair.
Although a number of other hallmarks of aging focus on processes that lead to deterioration of our cells, appropriate communication among cells and tissues is also important to maintaining health.
Hormones, for instance, are one way that cells communicate. Hormones produced in the brain alter the way cells behave in the rest of the body and vice versa. Your liver might chemically tell your brain to reduce hormone production or nerve cells that signal pain in your toe can chemically alert your immune system in the rest of your body. In relation to aging, perhaps the most important loss of appropriate communication in our bodies is the low-level, chronic inflammation that occurs as we grow older.
In youth, inflammation is mainly a response to infection or injury that is turned off once the infection has passed or the injury heals. In later life, low-level inflammation, infection- or injury-related, arises and becomes worse with age. This inflammation is damaging to normal tissue. Although the cause of age-related inflammation is unclear, considerable evidence points to senescent cells as one culprit.
Restoring proper intercellular communication could extend health by reducing chronic age-related inflammation. Additionally, investigators are studying how intercellular communication influences the rejuvenating properties of young blood; studies lend evidence that the blood of young animals contains molecules that can actually rejuvenate damaged heart, brain, and muscle in older adult animals. Also interesting, the blood of older animals may contain toxic molecules, which blood transfusion from younger animals may dilute.
Each cell in your body--except your red blood cells--contains the string of 3 billion DNA letters that defines your individual genome. Proper functioning of your genome is largely responsible for the smooth running of your body. However, your genome is under constant attack from both external sources such as radiation or pollution and internal sources such as oxygen free radicals.
By one estimate the DNA in each of your cells is damaged up to 1 million times per day. Fortunately, DNA also encodes a number of proteins that work together to detect and repair virtually all of this damage.
Still, repair is not perfect and as we age damage to our genome accumulates. Cancer is one result of unrepaired DNA damage. In both humans and mice, individuals with compromised DNA repair processes show multiple signs of accelerated aging. Many therapies whether dietary or pharmacological that extend life in mice enhance DNA repair processes and reduce the rate of DNA damage accumulation. Together, this is powerful evidence that genomic damage accumulation is fundamental to aging.
One specific type of genomic instability is telomere attrition. As it has received considerable individual attention, it will be mentioned separately. Telomeres are repetitive sequences of DNA that protect the ends of chromosomes and prevent them from being mistaken for broken DNA strands.
Telomere attrition, or shortening, is a specific type of DNA damage to the ends of chromosomes. Normal cell division shortens telomeres as do other processes that damage DNA. When telomeres reach a critically short length, cells sense it and permanently turn off their replication machinery.
An enzyme called telomerase, which is turned off in most adult cells, can prevent telomere shortening and even restore telomere length. Evidence linking telomere attrition to aging is that telomeres shorten with age in both people and mice. Mice genetically engineered to lack telomerase have shown some symptoms of premature aging, and mice engineered to express higher levels of telomerase than normal have been reported to live longer.
Inflammation is the body’s natural reaction to infection or injury, helping to kill the infection, repair the injury, and clean up the debris with cells and cocktails of molecules specialized for those roles.
Early in life inflammation performs these roles rapidly and then subsides as soon as the infection is gone, the injury repaired, the debris removed. However, with age, low level, persistent inflammation arises even in the absence of infection or injury. The constant presence of cells primed for killing and debris removal, inevitably leaking some of their destructive molecules, has damaging effects on surrounding cells and tissues leading to obvious problems such as arthritis and irritable bowel syndrome to less obvious problems like the lesions of cardiovascular disease and Alzheimer’s.
Also, this age-related constant inflammatory vigilance means that when a big burst of inflammation is needed to fight infection, repair a wound, or kill proto-cancer cells, for instance, the body is no longer capable of producing that burst.
There are multiple examples of experiments that show if we can reduce chronic inflammation it leads to health benefits.
We are covered with microbes of thousands of species. Collectively these are called our “microbiome.” About half of all the cells of your body in fact are not you, they are the bacterial cells that live on and in you. These bacteria are not passive passengers.
The ones in your gut (mouth to the other end), for instance, produce vitamins, hormones, and other substances critical for your continued health. Some also fight invading, potentially dangerous, bacteria.
They also are constantly exchanging health information with your own cells. Everyone’s microbiome is somewhat unique, depending on your genetics, lifestyle factors such as diet, and environment. Although the composition of your microbiome is fairly stable through early adulthood, it gradually changes becoming less diverse with aging, a process called dysbiosis.
The loss of diversity is associated with a number of the maladies of later life. Increasing the diversity of the aging microbiome with, say, fecal transplants from younger individuals, or the use of precise probiotics has been shown to have health benefits in both mice and humans.
Although we are just beginning to understand the complexities or our microbiome, this is an promising emerging area of aging research.
