When you think about your parents, relatives, friends, and acquaintances, you will notice that you know some very healthy and fit 60-year-old people and 60-year-old people that have trouble functioning in daily life.

Naturally, scientists are interested in finding out why some people age faster than others. One type of study that allows us to study aging is twin studies. In this type of study, the aging process of identical twins is studied; because these individuals are genetically identical, any differences are assumed to be due to external factors.

Twins that showed the greatest discrepancies in aging also had the greatest degree of discordance between personal lifestyle choices and habits. The most notable exogenous factors that influenced the degree of aging were sun exposure and smoking. Other contributors included excessive alcohol consumption, stress, diet, exercise, disease, and medications.

Twin studies indicate that the genetic influence on aging may be overrated, with lifestyle choices exerting far more important effects on physical aging. Once an unhealthy lifestyle results in obesity and chronic diseases, the aging process becomes even more accelerated.

Although we know what factors are linked to increased aging, we are just beginning to understand the metabolic processes that accelerate aging. The hope is, once we understand the metabolic processes of aging, we can find ways to slow the aging process down.

Here is an overview of what we know today.

Physiological Aging Is Ongoing Through Adulthood 

Decline of Bone Density Starts During the Third Decade of Life

Before you learn about the declining bone density during adulthood, you should quickly review a few facts about osteoporosis, bone remodeling, and the interaction between calcium and vitamin D from your Human Nutrition and Metabolism course:

When you read in the media about connections between dairy and bone strength, the science seems chaotic. Claims range from dairy prevents osteoporosis to dairy causes osteoporosis, all of course supported by “science”. To understand those seemingly contradictory statements, you need to understand how bone mineral density develops over a lifetime.

Infants are born with very soft and malleable bones. This allows the fetus to squish through the narrow birth canal. Right after birth, the deposition of minerals into the collagen structure of the bone begins and will last all through childhood and adolescence.

During adolescence, bone mineralization accelerates until peak bone mass—the highest level of bone mineralization a person can ever reach—is achieved. During this phase of life, the bones are continuously remodeled. Because bone-building osteoblast activity outpaces bone-dissolving osteoclast activity, the result is an increase in bone mineralization.

After peak bone mass is reached, bone mineralization plateaus for a short time (osteoblast activity = osteoclast activity) and then starts to decline very slowly until age 50 is reached. During this phase of slow bone loss, the bones are completely remodeled every 10 years, but bone dissolving osteoclast activity is now higher than osteoblast activity. After age 50, the loss of bone mass accelerates until the end of life.

Therefore, the main factor in determining if somebody will develop osteoporosis over a lifetime is the peak bone mass. The higher the peak bone mass of a young adult, the less likely it is that the person develops osteoporosis. Genetics control 80% of the variation in peak bone mass between individuals. For instance, small-boned individuals start out with less minerals to lose over a lifetime (one of the reasons why women, especially Asian women, have a higher risk for osteoporosis).

Optimal Calcium And Vitamin D Intake Combined With Exercise Ensure a High Peak Bone Mass And Slow Bone Loss

The genetically predetermined peak bone mass can only be reached with an adequate calcium and vitamin D intake, along with sufficient exercise.

To understand how those three factors work together to ensure bone strength, we need to realize that the bone is a storage site, a reservoir for calcium and other minerals. 99% of all calcium in the body and 85% of phosphorus is stored in the bone.

Calcium blood concentrations must be maintained within a narrow range to enable muscle contraction, nerve function and intracellular processes. If calcium intake is low and blood calcium levels fall, parathyroid hormone (PTH) acts on the osteoclasts, and calcium is released from the bone. If release of calcium from the bone storage site is ongoing the bone loses strength.

Children and adolescents must have an adequate intake of calcium to reach the highest peak bone mass possible which is best accomplished by eating dairy or dairy replacements (see calcium source table).

Adequate intake of calcium during the rest of the life will ensure that bone mass loss is as slow as possible; however, increased calcium intake will not replace bone mass that is already lost or was never reached during the first 20 years of life.

Adequate calcium intake alone is not sufficient though, as vitamin D deficiency contributes to bone loss. Calcitriol, the active hormone form of vitamin D, acts on the small intestine to increase calcium absorption from food when blood calcium levels fall. If circulating vitamin D blood levels are inadequate, calcitriol cannot be synthesized, and calcium will not be absorbed. The missing calcium in the blood will need to come from bones.

In addition to adequate calcium and vitamin D intake, weight bearing exercises, such as strength training and higher impact aerobic activities, stress the bone. This triggers repairs, and therefore better bone mineralization of the bone in all life stages.

In summary, genetics determine the maximal peak bone mass a person can reach; however, intake of calcium and vitamin D as well as exercise determine if the maximal peak bone mass is reached and how fast the bone mass is lost during life.

Two Phases of Life Are Especially Important to Maintain as Much Bone Mass as Long as Possible: Adolescence and Menopause

Adolescence: The key to osteoporosis prevention is reaching optimal peak bone mass. During this time of bone growth and mineralization, food needs to supply sufficient amounts of calcium, vitamin D, and other minerals such as potassium, magnesium and phosphorus. In addition, regular physical activity and exercise stresses bones and triggers better mineralization.

Infants and young children in the US drink sufficient amounts of milk. However, during teenage years—when bone mineralization accelerates—milk and dairy consumption tends to fall short. As a result, many teens do not get enough calcium to reach their genetically maximal peak bone mass. Another contributor to this issue is that today’s more sedentary lifestyle will not allow for optimal peak bone mass.

Menopause: During menopause the cessation of estrogen production stimulates osteoclast activity. Consequently, women will go through a phase of accelerated bone mass loss at and a few years after menopause. This short period of rapid bone mineral loss partially explains the higher risk for osteoporosis in women compared to men.

Interestingly, underweight young women and women with eating disorders will experience a decline of estrogen blood levels due to declining leptin levels. These women also show signs of accelerated bone loss similar to menopausal women independent of age. Once those underweight women gain weight, estrogen production resumes and bone mineralization normalizes. The bone loss or reduced bone mineralization cannot be reversed though and will increase the risk of developing osteoporosis later in life.

Ideally, Osteopenia Will Happen in High Age but Osteoporosis Never Will

Bone mineral density and osteoporosis are not cconditionsadolescents and younger adults think about. All individuals will, at one point during their lifespan, lose enough bone mass to develop low bone density, called osteopenia. It is just a question of longevity. The goal is to reach this point as late as genetically possible, and that osteoporosis with brittle bones and spontaneous fractures is never reached.

Low bone mass is diagnosed using a DEXA scan. Many women undergo a DEXA scan during or after menopause as a preventative measure to detect osteopenia. The general recommendation for both men and women is to undergo a DEXA scan after 65.

Low bone mass should be an alarm bell because—if bone loss keeps progressing—osteopenia will develop into osteoporosis along with an increased risk for fractures and loss of life quality as seen in the video clip below.

The diagnosis of osteopenia and/or osteoporosis should trigger lifestyle changes such as better calcium intake and increased exercise. Bone loss cannot be reversed with lifestyle changes, but further bone loss can be slowed down. Lately, bone loss reversing medication is available, and can help gain some bone mass back and avoid further loss.

Keep in mind that this situation can be easily prevented during childhood and adolescence.

Coming back to the seemingly confusing science, studies are clear that a good calcium intake from dairy and dairy replacements is necessary to reach genetically optimal peak bone mass during childhood and adolescence. Milk and many of the plant milks are also enriched with vitamin D. Exercise and outdoor activities complement the calcium intake. This needs to be separated from studies conducted in middle aged adults and seniors since for this group the goal is slowing down bone loss.

Maintaining Body Composition During Adulthood Is Hard Work

In Middle Age Body Fat Redistributes from Peripheral to Central Fat Stores, From Subcutaneous to Visceral

As %FM slowly increases during middle age, body fat redistributes from peripheral to central fat stores. There is also a shift from subcutaneous to visceral fat stores. As a result of these adjustments, waist circumference keeps increasing.

Before menopause, many women have a much lower amount of central adipose tissue compared to men; however, after menopause, waist circumference increases in women at the same rate as men. This is thought to be due to the loss of estrogen, which promotes a gynoid fat distribution (peripheral, subcutaneous) before menopause.

The image on the right of the infographic above compares a scan of the abdominal body fat distribution of an 82- and 37-year-old person. Both individuals have the same waist circumference. In this scan, muscles and organs are light gray while adipose tissue is dark gray. The 82-year-old (left) has less subcutaneous fat and more visceral fat (Kuk et al., 2009).

Menopause Equals the Playing Field for Men and Women

Menopause Marks the End of Fertility for Women and the Start of a Whole New Life

Before menopause, estrogen and progesterone levels rise and diminish in a distinct cyclical pattern, roughly every 28 days.

Estrogen increases during the first half of the menstrual cycle, growing the uterus lining and stimulating the maturation of an ovum in the ovary. When estrogen reaches its peak, ovulation takes place and progesterone production increases. If the ovum is not fertilized, both estrogen and progesterone production declines. These declining hormone levels trigger the shedding of uterus lining, the menstruation. After the menstruation, estrogen secretion increases, and the menstrual cycle starts over.

Starting in the 4th decade of life—though the start varies widely—women enter perimenopause. Perimenopause lasts several years and is marked by a less regular cyclical estrogen and progesterone pattern and lower hormone levels. The consequence is infrequent periods and reduced fertility. Because estrogen is involved in body temperature regulation, many women will also experience the famous hot flashes, which may lead to sleep problems. The intensity of these symptoms varies from woman to woman.

Perimenopause concludes with menopause. Menopause is defined as the point in life when ovulation stops completely. Women are considered menopausal if they do not have a period for more than a year.

Estrogen Has Many More Functions in Addition to Fertility

We usually associate estrogen with female fertility, but estrogen has other important regulatory roles. Once estrogen blood levels decline during perimenopause, physiological changes set in.

We already talked about estrogen and bone density maintenance. Estrogen is bone-protective. Declining estrogen blood levels stimulate bone-absorbing osteoclast activity and accelerate bone loss for several years after menopause. This is a non-modifiable physiological process. Once the woman is a few years past menopause, bone loss slows down to a steady decline—similar to the rate for men.

The lack of estrogen also has metabolic consequences. Estrogen tends to be cardioprotective. One average, pre-menopausal women have lower LDL cholesterol—and thus have a lower risk for CVD and heart attacks—compared to men. After menopause, women “catch up” to men, and are at the same risk level.

High blood levels of estrogen promote a pear-shaped body type. After menopause, women experience two changes:

1. It is much harder for women to maintain a healthy body weight
2. Body fat distribution shifts towards central obesity

These changes, higher weight and central obesity, increase the risk for chronic diseases.

Myth or Fact: Do Women Experience Cognitive Decline During Menopause?

No, this is definitively a myth!

Studies show a slight cognitive decline during menopause—but this is mostly due to other factors such as increasing BMI, the aging process, or other health issues—and not specific to women.

On a side note, there is one exception. After having a full hysterectomy, the surgical removal of the uterus and ovaries, women undergo induced menopause because the ovaries—normally producing estrogen and progesterone—are missing. If this happens early in life, for example when women are in their 20s and early 30s, studies show that those women are affected by some degree of cognitive decline. The earlier the artificially induced menopause takes place, the more noticeable the cognitive decline is.

Maybe the results from those studies led to the overall notion that menopause and cognitive decline are connected; however, a cognitive decline is not observed if women are undergoing a timely natural menopause in their late 40s and early 50s.

Is there such a thing as andropause? The menopause for men?
No, andropause is a myth! However, men do undergo a moderate gradual decline in testosterone secretion from the peak in the early 20s until age 40. This natural decline in middle age—and a potential further decline throughout later life—is highly variable between individual men. Declining testosterone increases the risk for weight gain and muscle mass loss.

Subtle Endocrine Decline Takes Place in Healthy Adults, but Is Not Well Researched

Beta-Cell Function Declines

You already learned about the decline of beta-cells in people with insulin resistance due to an unhealthy lifestyle and obesity.

Even in healthy active adults, the function of insulin-producing beta-cells in the pancreas declines 1% per year. When you look at the scatter plot to the right, you should notice a downward trend, but also huge individual differences (one dot represents one person).

Since research primarily focuses on pathological insulin resistance and T2D, research in healthy adults is slim. It is thought though that this physiological decline in beta-cell function with age is not due to increased cell death, as is the case with insulin resistance and T2D. Instead, the functional decline seems to be due to reduced cell proliferation (cell division and growth). This is not unique to beta-cells; the regenerative capacity of cells decreases with age for most organs.

Due to declining beta-cell function, the risk of developing T2D increases with age in healthy adults. This age-effect is relatively small compared to the effect of weight and a sedentary lifestyle. Decreasing insulin sensitivity is much more connected to an increasing BMI, or more precisely, to an increasing waist circumference.

Growth Factor and IGF-1 decline

Growth hormone and IgF-1, both necessary for growth and organ maintenance, reach a peak around 20 years of age. After reaching a peak, both steadily decline during adulthood; however, the consequences of this decline are not clear.

Decreasing growth hormone is discussed as a potential reason for a decline in lean body mass.

On the other hand, high IgF-1 levels are not desirable and are considered a risk factor for some cancers. Centenarians tend to have very low IgF-1 blood levels and scientists wonder if this is protective against cancer and other chronic diseases.

Feasting and high-protein diets increase IgF-1 blood levels. This is what led to wild media claims such as “high protein diets increase the risk for cancer” and “regular fasting results in longevity.” These connections were only observed in animal research, while in humans a slightly higher weight in high age seems to be more beneficial. More about that later.

It will be interesting to see where this research goes, but at this point, it is too early to start fasting for longevity or eating a low-protein diet to reduce IgF-1.

Going Deeper: Cellular Aging Affects Virtually Every Aspect of Cell Biology

There are various physiological changes we can evaluate when assessing aging: determining body composition, drawing blood to measure and array of metabolic markers, and measuring hormone blood levels. When we do this, we see that everything becomes less efficient with age.

Part of this decline can be explained by an increase of ectopic fat in organs; however, this does not explain the subtle decline of insulin production, the speeding up of atherosclerosis, or the decline of cognition during the senior years. For that, we need to dig deeper to the cellular level.

You may have read that eating a certain diet or taking a range of supplements might slow down aging. All those claims tend to center around antioxidants. Garlic and vitamin E were the first—and most popular—anti-aging supplements, until it was discovered that high doses of vitamin E can lead to brain bleeds.

Today, turmeric, EGCG from green tea, anthocyanins from red wine, or flavonols from dark chocolate are touted as the life-prolongers. What they all have in common is that they are anti-inflammatory. This is where a kernel of truth lies: when the aging process is examined at the cellular level, inflammation—measured, for example, by cytokine blood levels—increases with age.

Inflammaging: Cellular Aging Increases Inflammation

Research in animal models and human cell studies has demonstrated that aging affects all aspects of cell biology, likely due to the physical and chemical damage that happens throughout a lifetime.

The sources for this cell damage are either endogenous (for example, due to free radical production during cell metabolism) or exogenous (for example, due to external sources such as overnutrition, sun exposure, smoking, and excessive alcohol consumption). The constant attempts to repair this ongoing damage to cells and DNA exhaust the molecular mechanisms over time, and eventually errors are made. It is like a car you drive for 10 years; the components of the motor will experience wear and tear. Material weakens, and at one point breaks down.

Mitochondria Dysfunction: during normal energy metabolism, oxidants called “reactive oxidant species” or ROS are produced in the mitochondria as an unavoidable side product. ROS are strong oxidants and grab electrons from fatty acids in the mitochondrial membranes.

Recall the energy metabolism process, especially the electron transport chain:

The inner mitochondrial membrane is the location of the electron transport chain, which is essential to the production of ATP. The electron transport chain functions by separating protons and electrons from NADH+H and FADH2, and then transporting the protons across the inner cell membrane. The electrons are handed along protein carriers sitting in the inner cell membrane. This builds up an electrochemical gradient. The energy of this gradient is used to drive the oxidative phosphorylation of ADP to ATP.

Damage to the inner mitochondrial membrane leads to alterations in the function of the electron transport chain. Damage to other mitochondria membranes leads to a reduction in transport of critical metabolites, such as fatty acids, pyruvate, NADH+H into mitochondria.

Consequently, less ATP is produced, and the person with mitochondrial dysfunction will experience more (and faster) fatigue.

Mitochondrial dysfunction increases the risk for CVD, T2D, and the neurodegenerative chronic diseases of old age such as cognitive decline, dementia, or Alzheimer’s disease. On the other hand, chronic diseases can induce mitochondrial dysfunction at any age.

In mice studies, fasting or intense exercise seems to reduce ROS. Less ROS production allows mitochondria to function better and longer. This is the reason you may sometimes read that fasting will increase longevity.

Interestingly, this is not necessarily true for humans. You will learn during the next chapter that old individuals will age better if they have a BMI in the overweight category. There is no scientific explanation for this puzzling discrepancy so far.

ER Stress: the endoplasmic reticulum (ER) is a cell organelle involved in the folding of proteins, after amino acid chains are produced on the ribosomes. Just like the mitochondria, the ER experiences oxidative stress over time.

Damage to the walls of the ER results in a reduced capacity to fold proteins. Increasing amounts of misfolded proteins aggregate in the cell because the garbage disposal of the cell, autophagy, is also affected by the aging process and becomes less efficient. This accumulation of garbage—this is the actual scientific terminology—triggers an inflammatory response, which increases chronic inflammation.

We think that those processes contribute to the age-related onset of chronic diseases such as T2D, CVD, or cancer.

DNA Damage: the DNA has now experienced 60-80 years of damage and repair. Some of those repairs were not successful. Mistakes while copying the DNA or the epigenome are carried forward to the daughter cells during further cell divisions.

Copy mistakes lead to gene mutations, and these in turn can produce increased amounts of neoplastic cells, cells with abnormal growth. Most neoplasms are detected by the immune system and removed. As cells age, more abnormal cells form and with an aging immune system, more escape to grow into benign or malignant tumors. The risk for cancer increases.

Independent from oxidative damage, telomeres (the protective caps at the tip of chromosomes) wear down gradually with every cell division. This is called telomere attrition. Over time, the telomeres become shorter and shorter, until the chromosomes cannot divide anymore. This will lead to apoptosis (cell death).

Damaged organelles, misfolded proteins, impaired disposal of cellular garbage, and increasing amounts of neoplastic cells due to cellular aging all trigger the innate immune system. Recall that the innate immune system is always triggered if a molecule is detected that should not be there. Chronic inflammation increases. This process is dubbed inflammaging, and can be determined by measuring the increased proinflammatory cytokines in the blood.

Glucotoxicity and Lipotoxicity Accelerate Cellular Aging

In module one, you learned that certain conditions (metabolic syndrome, insulin resistance, T2D, and CVD) often come with elevated free fatty acid and glucose blood concentrations. Both elevated fatty acids and glucose are toxic to cells, but what exactly does “glucotoxic” and “lipotoxic” mean?

An overabundance of glucose and free fatty acids leads to over fueling of the mitochondria. Since reactive oxygen species (ROS) are a byproduct of mitochondrial metabolism, increased amounts of ROS are formed. This overabundance will also trigger the rerouting of free fatty acids and glucose to alternative metabolic pathways, accumulating products that add to the cellular stress. Lastly, both ectopic fat and glycosylated proteins form, and further contribute to cellular stress.

Increased cellular stress sends the cell into a vicious cycle. Mitochondria function at reduced capacity and ATP production declines; as a result, affected individuals will quickly tire out. As the immune system and other metabolic functions decline, ER stress will lead to increased accumulation of cellular garbage and cellular signaling, eventually leading to increased cell death (apoptosis).

Consequently, systemic inflammation increases, which then increases the risk for T2D, CVD, non-alcoholic fatty liver disease, and reduced cognitive functioning. In short, all body systems are affected.

Genetic Predisposition and Lifestyle Choices Interact to Accelerate or Slow Aging

Inflammaging sounds more dramatic than it is. In healthy active adults and seniors, these processes are ongoing, but occur at a slow pace.

Cellular aging decreases the functionality of organs and increases the risk for age-related chronic diseases, but centenarians live a long life despite cellular aging processes. A positive, relaxed life in combination with a healthy lifestyle, including lots of physical activity and a plant-heavy diet, seems to stem the tide.

Cellular aging, combined with a genetic predisposition for chronic diseases and an unhealthy lifestyle, is a different story.

As discussed in module one, most chronic diseases—such as T2D and CVD—and cancer develop when a genetic predisposition meets increased chronic systemic inflammation, often due to obesity and an unhealthy lifestyle. If chronic systemic inflammation is already ongoing, it adds to cellular aging and aggravates physiological inflammaging. As a result, the aging process and development of chronic diseases speed up.

Back to Epigenetics: The Epigenome Changes Over a Lifetime

We know that many obese people develop age-related changes much earlier than others, and that developing chronic diseases can speed up aging tremendously. So, the question is: how is aging sped up? One explanation is chronic systemic inflammation, but there is another explanation you already learned about: changes to the epigenome.

It is thought that the key to changes of the DNA methylation pattern is lifestyle. During the epigenetics unit, you learned that sufficient amounts of methyl tags are necessary to duplicate epigenetic marks during cell division, or to increase methylation to suppress less desirable phenotypes. Dietary intake of fiber and phytochemicals (from vegetables, soy, tea, and fruits) is beneficial for the gut microbiome, and influences the epigenetic machinery positively. Exercising also positively regulates this machinery. 

Overnutrition can increase histone acetylation, which has the opposite effect. By adding more acetyl groups to histone tails, stretches of DNA become available for transcription.

These two explanations—inflammation and epigenetic changes due to lifestyle—are the beginning of explaining the diverse speed of the aging process. Scientists are still working on figuring out why some individuals age faster than others, and why an increasingly larger group of people seems to age extremely slowly. The goal of research in this area is to add as many healthy years to peoples’ lives as possible.

The Key to Longevity? Dodging Chronic Diseases and Cognitive Decline

This closes the circle, bringing us back to the paradigm of the life cycle nutrition approach: The key to a long and healthy life is avoiding chronic diseases as long as genetically possible

As you have seen, the prevention of chronic diseases begins before birth and depends on mother’s behavior during pregnancy. This process continues after birth as a healthy metabolism is set by the feeding decisions parents make, and later the health behaviors learned from parents. Practicing a healthy lifestyle—or starting it during young adulthood—will reduce not only the risk for chronic diseases, but also slow the aging process as much as possible.

Overall, the contribution of our genes to aging is estimated to be 15-30%. The rest comes from our lifestyle decisions throughout life.

It should be clear that the speed of aging progression varies substantially. Therefore, rather than making assumptions and generalizing treatment for this age group, health care professionals should treat the heterogenous group of seniors on an individual basis.