Aging under the Microscope

Section 1.1: What Is Aging?

This section includes text excerpted from “Biology of Aging—Aging under the Microscope,” National Institute on Aging (NIA), National Institutes of Health (NIH), January 21, 2017.

The Aging Process

We may want to live forever, but who looks forward to getting old? We hope we're vigorous right up until the very end. Still, day-to-day, many of us make unhealthy choices that could put our future at risk.

From the beginning of time, people have tried to understand aging. Almost every culture has a mythology to explain it. As we grow up, tales of eternal youth pique our curiosity. And, it is these musings that may provide just the spark needed to ignite a budding scientist. There's the little girl, excited to visit her grandmother, who asks her parents how someone so spunky and fun could be so old. Or, the 3rd grader who, after watching in awe as a caterpillar spins a cocoon and then days later emerges as a butterfly, peppers the teacher with questions about this magical transformation. These are the types of questions and kinds of experiences that could stimulate a lifelong quest to explore what happens as we age.

Technology today supports research that years ago would have seemed possible only in a science fiction novel. Over centuries, theories about aging have emerged and faded, but the true nature of the aging process is still uncertain. The fact is—aging is a part of everyone's life. But the facts of aging—what is happening on a biochemical, genetic, and physiological level—remain rich for exploration.

What Aging Means

Gerontologists look for what distinguishes normal aging from disease, as well as explore why older adults are increasingly vulnerable to disease and disability. They also try to understand why these health threats take a higher toll on older bodies. Since 1958, NIA's Baltimore Longitudinal Study of Aging (BLSA) has been observing and reporting on these kinds of questions. As with any longitudinal study, the BLSA repeatedly evaluates people over time rather than comparing a group of young people to a group of old people, as in a cross-sectional study. Using this approach, BLSA scientists have observed, for example, that people who have no evidence of ear problems, or noise-induced hearing loss, still lose some of their hearing with age—that's normal. Using brain scans to learn if cognitive changes can be related to structural changes in the brain, BLSA scientists discovered that even people who remain healthy and maintain good brain function late in life lose a significant amount of brain volume during normal aging.

However, some changes that we have long thought of as normal aging can be, in fact, the signs of a potential disease. Take, for example, sudden changes in personality. A common belief is that people become cranky, depressed, and withdrawn as they get older. But an analysis of long-term data from the BLSA showed that an adult's personality generally does not change much after age 30. People who are cheerful and assertive when they are younger will likely be the same when they are age 80. The BLSA finding suggests that significant changes in personality are not due to normal aging, but instead may be early signs of disease or dementia.

Scientists are increasingly successful at detailing these age-related differences because of studies like the BLSA. Yet studies that observe aging do not identify the reasons for age-related changes, and, therefore, can only go so far toward explaining aging. Questions remain at the most basic level about what triggers aging in our tissues and cells, why it occurs, and what are the biological processes underlying these changes. Scientists look deep into our cells and the cells of laboratory animals to find answers. What they learn today about aging at the cellular and molecular levels may, ultimately, lead to new and better ways to live a longer, healthier life.

Section 1.2: Genetics: Is Aging in Our Genes?

This section includes text excerpted from “Biology of Aging—Genetics: Is Aging in Our Genes?” National Institute on Aging (NIA), National Institutes of Health (NIH), January 21, 2017.

You may get your hair color from your father's side of the family and your great math skills from your mother. These traits are “in the genes,” so to speak. Likewise, longevity tends to “run in families”—your genetic makeup plays an important role in how you age. You can see evidence of this genetic connection in families with siblings who live into their 90s or families that have generation after generation of centenarians. These long-lived families are the basis for many genetic studies.

Identifying the genes associated with any trait is difficult. First, just locating the gene requires a detailed understanding of the trait, including knowledge of most, if not all, of the contributing factors and pathways related to that trait. Second, scientists must have clear ways of determining whether the gene suspected to have a relationship with the trait has a direct, indirect, or even no effect on that trait.

Identifying longevity genes is even more complex than determining genes for height or hair color, for example. Scientists do not know all the factors and pathways that contribute to longevity, and measuring a gene's effect on long-lived animals, including humans, would literally take a lifetime! Instead, scientists have identified hundreds of genes that affect longevity in short-lived animal models, like worms and flies. Not all of these genes promote long life. Sometimes mutating or eliminating a gene, increases lifespan, suggesting that the normal function of the gene limits longevity. Findings in animal models point to places for scientists to look for the genes that may influence longevity in humans.

How Can We Find Aging Genes in Humans?

The human genetic blueprint, or genome, consists of approximately 25,000 genes made up of approximately 3 billion letters (base pairs) of deoxyribonucleic acid (DNA). Small deviations in the base pairs naturally occur about once in every 1,000 letters of DNA code, generating small genetic variants. Scientists are finding that some of these variants (polymorphisms) are actually associated with particular traits or chance of developing a specific disease. People with a certain trait, for example, those living past age 100, may be more likely to have one variant of a gene, while people without the same trait may be more likely to have another variant. While it is very difficult to prove that a gene influences aging in humans, a relationship, or “association,” may be inferred based upon whether a genetic variant is found more frequently among successful agers, such as centenarians, compared with groups of people who have an average or short lifespan and healthspan.

Several approaches are used to identify possible genes associated with longevity in humans. In the candidate gene approach, scientists look for genes in humans that serve similar functions in the body as genes already associated with aging in animal models, so-called “homologs” or “orthologs” to animal genes. For instance, after finding longevity genes involved in the insulin/IGF-1 pathway of animal models, researchers look for the comparable genes in the insulin/IGF-1 pathway of humans. Scientists then determine whether the genes are linked to longevity in humans by looking to see if a variant of the genes is prevalent among people who live healthy, long lives but not for people who have an average healthspan and lifespan.

Another approach, the genome-wide association study, or GWAS, is particularly productive in finding genes involved in diseases and conditions associated with aging. In this approach, scientists scan the entire genome looking for variants that occur more often among a group with a particular health issue or trait. In one GWAS study, NIH-funded researchers identified genes possibly associated with high and low blood fat levels, cholesterol, and, therefore, risk for coronary artery disease. The data analyzed were collected from Sardinians, a small genetically alike population living off the coast of Italy in the Mediterranean, and from two other international studies. The findings revealed more than 25 genetic variants in 18 genes connected to cholesterol and lipid levels. Seven of the genes were not previously connected to cholesterol/lipid levels, suggesting that there are possibly other pathways associated with risk for coronary artery disease. Heart disease is a major health issue facing older people. Finding a way to eliminate or lower risk for heart disease could have important ramifications for reducing disability and death from this particular age-related condition.

Scientists are also currently using GWAS to find genes directly associated with aging and longevity. Because the GWAS approach does not require previous knowledge of the function of the gene or its potential relationship with longevity, it could possibly uncover genes involved in cellular processes and pathways that were not previously thought to play roles in aging. Since no single approach can precisely identify each and every gene involved in aging, scientists will use multiple methods, including a combination of the GWAS and candidate gene approaches to identify genes involved in aging.

Section 1.3: Metabolism: Does Stress Really Shorten Your Life?

This section includes text excerpted from “Biology of Aging—Metabolism: Does Stress Really Shorten Your Life?” National Institute on Aging (NIA), National Institutes of Health (NIH), August 21, 2017.

What Stress Is

Have you ever looked at side-by-side photos of a person before and after a particularly trying time in his or her life, for instance, before and a few years after starting a highly demanding job? The person likely appears much older in the later photo. The stress of the job is thought to contribute to the prematurely aged appearance. You might feel stress from work or other aspects of your daily life, too. Stress is everywhere. Even when you feel relaxed, your body is still experiencing considerable stress—biological stress. And, it is this type of stress that is widely studied by gerontologists for its effects on aging and longevity.

Biological stress begins with the very basic processes in the body that produce and use energy. We eat food and we breathe, and our body uses those two vital elements (glucose from food and oxygen from the air) to produce energy, in a process known as metabolism. You may already think of metabolism as it pertains to eating—“My metabolism is fast, so I can eat dessert,” or “My metabolism has slowed down over the years, so I'm gaining weight.” Since metabolism is all about energy, it also encompasses breathing, circulating blood, eliminating waste, controlling body temperature, contracting muscles, operating the brain and nerves, and just about every other activity associated with living.

These everyday metabolic activities that sustain life also create “metabolic stress,” which, over time, results in damage to our bodies. Take breathing—obviously, we could not survive without oxygen, but oxygen is a catalyst for much of the damage associated with aging because of the way it is metabolized inside our cells. Tiny parts of the cell, called mitochondria, use oxygen to convert food into energy. While mitochondria are extremely efficient in doing this, they produce potentially harmful by-products called oxygen free radicals.

Free Radicals and Aging

A variety of environmental factors, including tobacco smoke and sun exposure, can produce them, too. The oxygen free radicals react with and create instability in surrounding molecules. This process, called oxidation, occurs as a chain reaction: the oxygen free radical reacts with molecule “A” causing molecule “A” to become unstable; molecule “A” attempts to stabilize itself by reacting with neighboring molecule “B”; then molecule “B” is unstable and attempts to become stable by reacting with neighboring molecule “C”; and so on. This process repeats itself until one of the molecules becomes stable by breaking, or rear-ranging itself, instead of passing the instability on to another molecule.

Some free radicals are beneficial. The immune system, for instance, uses oxygen free radicals to destroy bacteria and other harmful organisms. Oxidation and its by-products also help nerve cells in the brain communicate. But, in general, the outcome of free radicals is damage (breaks or rearrangements) to other molecules, including proteins and deoxyribonucleic acid (DNA). Because mitochondria metabolize oxygen, they are particularly prone to free radical damage. As damage mounts, mitochondria may become less efficient, progressively generating less energy and more free radicals.

Scientists study whether the accumulation of oxidative (free radical) damage in our cells and tissues over time might be responsible for many of the changes we associate with aging. Free radicals are already implicated in many disorders linked with advancing age, including cancer, atherosclerosis, cataracts, and neurodegeneration.

Fortunately, free radicals in the body do not go unchecked. Cells use substances called antioxidants to counteract them. Antioxidants include nutrients, such as vitamins C and E, as well as enzyme proteins produced naturally in the cell, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase.

Section 1.4: Immune System: Can Your Immune System Still Defend as You Age?

This section includes text excerpted from “Biology of Aging—Immune System: Can Your Immune System Still Defend You as You Age?” National Institute on Aging (NIA), National Institutes of Health (NIH), August 21, 2017.

Immune System and Its Functions

Elementary schools are breeding grounds for the common cold. Kids pass their germs around as often as they share their lunch. For children, catching a cold may not be a big deal. They might take it easy for a few days while their immune system kicks into action and fights off infection. But for their older teachers and grandparents, each cold can be more of a challenge. It may take a week, or longer to get back to feeling 100 percent. Does that mean that the immune system gets weaker as we age? That's what gerontologists are trying to figure out.

Innate immunity is our first line of defense. It is made up of barriers and certain cells that keep harmful germs from entering the body. These include our skin, the cough reflex, mucous membranes, and stomach acid. If germs are able to pass these physical barriers, they encounter a second line of innate defense, composed of specialized cells that alert the body of the impending danger. Research has shown that, with age, innate immune cells lose some of their ability to communicate with each other. This makes it difficult for the cells to react adequately to potentially harmful germs called pathogens, including viruses and bacteria.

Immune System and Inflammation

Inflammation is an important part of our innate immune system. In a young person, bouts of inflammation are vital for fighting off disease. But as people age, they tend to have mild, chronic inflammation, which is associated with an increased risk for heart disease, arthritis, frailty, type 2 diabetes, physical disability, and dementia, among other problems. Researchers have yet to determine whether inflammation leads to disease, disease leads to inflammation, or if both scenarios are true. Interestingly, centenarians and other people who have grown old in relatively good health generally have less inflammation and a more efficient recovery from infection and inflammation when compared to people who are unhealthy or have average health. Understanding the underlying causes of chronic inflammation in older individuals—and why some older people do not have this problem—may help gerontologists find ways to temper its associated diseases.

The adaptive immune system is more complex than the innate immune system and includes the thymus, spleen, tonsils, bone marrow, circulatory system, and lymphatic system. These different parts of the body work together to produce, store, and transport specific types of cells and substances to combat health threats. T cells, a type of white blood cell (called lymphocytes) that fights invading bacteria, viruses, and other foreign cells, are of particular interest to gerontologists.

A healthy young person's body is like a T cell producing engine, able to fight off infections and building a lifetime storehouse of memory T cells. With age, however, people produce fewer naïve T cells, which makes them less able to combat new health threats. This also makes older people less responsive to vaccines, because vaccines generally require naïve T cells to produce a protective immune response. One exception is the shingles vaccine. Since shingles is the reactivation of the chickenpox virus, this particular vaccine relies on existing memory T cells and has been particularly effective in older people. Researchers are investigating ways to develop other vaccines that are adjusted for the changes that happen in an older person's immune system.

Negative, age-related changes in our innate and adaptive immune systems are known collectively as immunosenescence. A lifetime of stress on our bodies is thought to contribute to immunosenescence. Radiation, chemical exposure, and exposure to certain diseases can also speed up the deterioration of the immune system. Studying the intricacies of the immune system helps researchers better understand immunosenescence and determine which areas of the immune system are most vulnerable to aging. Ongoing research may shed light on whether or not there is any way to reverse the decline and boost immune protection in older individuals.

  This information is not a tool for self-diagnosis or a substitute for professional care.