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our epigenome changes as we age--levers are lost, added inappropriately, or shifted around. As a result, precise coordination of gene activity can be compromised. One particularly well-studied group of molecules that influence the epigenome is the sirtuins, molecules that remove one type of epigenetic handle. Interestingly, our 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 when mice are made deficient in one of the seven mouse sirtuins, they show signs of accelerated aging. Moreover, when that same sirtuin is superabundant, male mice live longer.
Loss of Proteostasis
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.
With age proteins get damaged by normal cellular processes 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.
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.
Deregulated Nutrient Sensing
When nutrients are abundant, animals including humans grow and reproduce--the evolutionary imperative. When nutrients are scarce, evolution has designed animals to focus on maintenance and repair.
Studies have been designed to inhibit the signalling of nutrient abundance by reducing food, 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, the insulin-like growth factor
All of these strategies enhance health and longevity in mice and other species.
Mitochondria—often called the “powerhouses of the cell”— places where most of our 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 our 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 signalling cellular stress.
Cells that once replicated vigorously but have now entered a permanent nondividing state are called senescent cells. We accumulate senescent cells with age. These cells do not die. 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. Work is now underway to identify drugs that target senescent cells for destruction.
Stem Cell Exhaustion
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.
Altered Intercellular Communication
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 are one of the ways cells communicate. Hormones produced in the brain alter the way cells behave in the rest of the body and vice versa. Our liver might chemically tell our brain to reduce hormone production or nerve cells that signal pain in our toe can chemically alert our immune system in the rest of our 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 injury that is turned off once the injury heals. In later life, low-level inflammation is not injury-related, but constant. Moreover, this inflammation is damaging to surrounding tissue. Although the cause of age-related inflammation is unclear, considerable evidence points to senescent cells as the culprit.
Restoring proper intercellular communication could extend health by reducing chronic age-related inflammation.
Proper functioning of our genome is largely responsible for the smooth running of our body. However, our 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 our cells is damaged up to 1 million times per day. Fortunately, DNA also encodes a number of processes that detect and repair virtually all of this damage.
Still, repair is not perfect and as we age damage to our genome accumulates. In both humans and mice, individuals with compromised DNA repair processes show multiple signs of accelerated aging and that therapies such as dietary restriction reduce the rate of DNA damage accumulation: this gives evidence that genomic accumulation is fundamental to aging.
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.