When you think about your parents, relatives, your friends and acquaintances you will notice that you know some very healthy and fit 60-year old people and other 60-year old people that have trouble functioning in daily life.
Naturally, scientists are interested to find out why some people age faster than others. One type of study that allows us to study aging are twin studies. You recruit sets of identical twins and study their aging process.

The scientists hypothesize that since these individuals are genetically identical, any differences found should be the result of external factors. The studies found exactly that. 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 influencing the degree of aging were sun exposure and smoking. Other contributors included excessive alcohol consumption, stress, diet, exercise, disease, and medications.

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.

Overall we know what factors are linked to increased aging, but we are just at the 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 to 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 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 even 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, but bone building osteoblast activity outpaces bone dissolving osteoclast activity by far. 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.

This makes it clear that the main determinant if somebody will develop osteoporosis over a lifetime or not 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.

What controls the peak bone mass? Genetics control 80 % of the variation in peak bone mass between individuals. Small boned individuals have less minerals to lose over a lifetime to begin with. This is one of the reasons why women have a higher risk for osteoporosis and Asian women are at an especially high risk.

The genetically predetermined peak bone mass can only be reached with an adequate calcium and vitamin D intake along with sufficient exercise. Only if children and adolescents have an adequate intake of dairy or dairy replacements (see calcium source table below in the textbox) and are regularly exposed to sunlight, the genetically determined maximal peak bone mass can be reached.

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

To understand this, 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.

If calcium intake is low and blood calcium levels fall—it is essential that the body maintains a steady calcium blood level to enable nerve function, muscle contraction just to name a few—parathyroid hormone (PTH) acts on the osteoclasts and calcium is released from the bone.

Adequate calcium intake alone is not sufficient though. We also need to produce or ingest adequate amounts of vitamin D. Vitamin D can either come from UV exposure or the diet and is essential to synthesize calcitriol, the active hormone form of vitamin D, in response to low blood calcium levels. Calcitriol will act on the small intestine and increase the amount of calcium absorbed from food. 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. This way vitamin D deficiency will contribute to bone loss.

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 summary genetics determine the maximal peak bone mass a person can reach. 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 the 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. US Infants and young children drink sufficient amounts of milk. But, during teenage years when bone mineralization accelerates, milk and dairy consumption tends to fall short. As a consequence many teens do not get sufficient amounts of calcium to reach their genetically maximal peak bone mass.

In addition, regular physical activity and exercise stresses bones and triggers better mineralization. Today, the common sedentary lifestyle will not allow for optimal peak bone mass.

Menopause: During menopause the cessation of estrogen production stimulates osteoclast activity. Consequentially, women will go through a phase of accelerated bone mass loss at menopause and a few years after menopause. This short period of fast bone mineral loss explains part of the higher risk for osteoporosis women have 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 menopause 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 to develop osteoporosis later in life.

Ideally, osteopenia will happen in high age and osteoporosis never will

All individuals will at one point during their lifespan lose enough bone mass to develop low bone density called osteopenia. It’s just a question of longevity. The goal is that this point is reached 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.

If bone mass is low it should be an alarm bell, because if bone loss keeps progressing osteopenia will develop into osteoporosis with an increased risk for fractures and loss of life quality as seen in the video clip below. The diagnosis of osteopenia, and of course osteoporosis, should trigger lifestyle changes such as better calcium intake and increased exercise. Bone loss cannot be reversed with lifestyle changes. Only further bone loss can be slowed down. Bone loss reversing medication is lately available and can help to gain some bone mass back and avoid further losses. Keep in mind that this situation can be easily prevented during childhood and adolescence.

Osteoporosis Impacts Quality of Life Severely

Bone mineral density and osteoporosis are not conditions most adults think about. Watch the following video to see how osteoporosis can impact quality of life.

What is an excellent calcium source? 

When we look at  calcium content in foods we see that aside of milk and dairy some leafy greens look promising as calcium sources. It is important though to keep calcium bioavailability and usual servings sizes in mind when judging food sources.

Many leafy greens contain good amounts of calcium but also oxalic acid. Oxalic acid binds calcium and makes it unavailable for absorption. The table shows how much calcium is in a cup of the food, the bioavailability, and how much food would be necessary to replace 1 cup of milk with other food source for calcium. Keep in mind that 3 cups of milk are recommended per day for sufficient calcium intake for adults.

It becomes clear while vegetables contribute to calcium intake it is very difficult to get the recommended amount of calcium from vegetables alone. Who can eat 12 cups white beans or 9 cups kale each day. If dairy consumption is not possible due to lactose-intolerance fortified foods need to be considered.

Maintaining Body Composition During Adulthood Is Hard Work

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

Not only does %FM slowly increase, but in 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 waist circumference keeps increasing.

Before menopause many women have much lower amounts of central adipose tissue than men, but after menopause waist circumference increases at the same rate in women than 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, adipose tissue is dark-gray. Clearly, the 82 year old on the 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 raise and ebb in a distinct cyclical pattern roughly every 28 days.

Estrogen raises 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 it’s 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—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.

Since estrogen is involved in body temperature regulation many women will also experience the famous hot flashes leading to sleep problems. The intensity of those symptoms vary from woman to woman.

Perimenopause concludes with the 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 an non-modifiable physiological process.

A couple of decades ago women were routinely prescribed supplemental estrogen to slow down the bone loss and reduce symptoms of menopause until studies connected this treatment with an increased cancer risk.

Once the woman is a few years past menopause, the bone loss slows down to a steady decline similar to men’s again.

Metabolically, the lack of estrogen has consequences. Estrogen tends to be cardioprotective. Pre-menopausal women tend to have lower LDL cholesterol, and have a lower risk for CVD and heart attack then men. After menopause women catch up to men being now at the same risk level.

High blood levels of estrogen promote a pear-shaped body type. After menopause women experience two changes. It is much harder for women to maintain a healthy body weight and the body fat distribution shifts towards a more central obesity. Higher weight and central obesity increases the risk for chronic diseases.

Myth or Truth: Do Women Experience Cognitive Decline During Menopause? Myth!

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 is the cognitive decline.

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

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 if people develop insulin resistance due to an unhealthy lifestyle and obesity.

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

Since the research focus is mainly 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 we see in insulin resistance and T2D. Instead the decline of function seems to be due to reduced cell proliferation (reduced cell division and growth). This is not unique to beta-cells. The regenerative capacity of cells decreases with age for most organs.

Due to the declining beta-cell function the risk to develop T2D increases with age in healthy adults. The age-effect is relatively small though 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 and then steadily decline during adulthood. The consequences of this drop in blood levels are not clear.

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

On the other hand higher IgF-1 is not desirable since it is 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.

By the way, feasting and high-protein diets increases IgF-1 blood levels. That’s were the wild guesses in the media come from that high protein diets increase the risk for cancer and regular fasting results in longevity. These connections were solely observed in animal research. 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 is going, but at this point it is to early to start fasting for longevity or eat a low-protein diet to reduce IgF-1.

How about the “leaky” gut?

Many middle aged adults complain about food intolerance and media, blogs and webpages earn a lot of money peddling diets and supplements for that. What does the research say? Does the leaky gut promoting food intolerance during adulthood exist? Just as any other organ the capacity of the GI system to regenerate epithelial cells declines slowly during the aging process. This can weaken the tight junctions between epithelial cells. As a consequence the gut barrier is weakend and more macro molecules can pass through the epithelium. When it comes to “being leaky” the research is brand new, but so far it seems in healthy people this is not an issue. Much more discussed is the interplay between dysbiosis (an unhealthy bacteria composition in the colon), the immune system, and damage to the gut epithelium. It is not clear exactly how, but this leads to a reduction of gut barrier function and is connected to an array of diseases.

Going Deeper: Cellular Aging Effects 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. But this does not explain the subtle decline of insulin production or 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 ant-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-inflammatories. This is where a kernel of truth lies. When we look at the aging process at the cellular level inflammation—measured for example by the cytokine blood levels—is increasing with age.

Inflammaging: Cellular Aging Increases Inflammation

Research in animal models and human cell studies made it clear that aging affects all aspects of cell biology. It is thought that this is 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 but also 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 errors are made. It’s like a car you drive for 10 years. The components of the motor experience wear and tear. Material weakens and at one point breaks down.

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

Recall the energy metabolism, especially the electron transport chain:

The inner mitochondria 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 a electrochemical gradient. The energy of this gradient is used to drive the oxidative phosphorylation of ADP to ATP.

Damage to the inner mitochondria 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.

The consequence is that less ATP is produced and the person with mitochondrial dysfunction will experience more and faster fatigue.

Mitochondrial dysfunction is also a contributor to the neurodegenerative chronic diseases of old age such as cognitive decline, dementia, or Alzheimer’s disease and is increasing risk for CVD and T2D. On the flip side 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 why you read sometimes 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 is a cell organelle involved in the folding of proteins after aminoacid chains are produced on the ribosomes. Just like mitochondria the endoplasmatic riticulum experiences oxidative  stress over time.

Damage to the walls of the ER result in a reduced capacity to fold proteins. The 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 less efficient. This accumulation of garbage—it’s actually called that way scientifically—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, 70, 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 of those 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 cell garbage, and more 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 which can be determined by measuring the increased proinflammatory cytokines in the blood.

Glycotoxicity and Lipotoxicity Accelerate Cellular Aging

In module 1 you learned that metabolic syndrome, insulin resistance, T2D and CVD tend to come with elevated free fatty acid and glucose blood concentrations. Both elevated FAs and glucose are toxic to cells. What does glucotoxic and lipotoxic means though?

The overabundance of glucose and free fatty acids lead to overfuelling of the mitochondria. Since rective oxygen species or ROS are a by-product of metabolism in the mitochondria increased amounts of ROS are formed.

The abundance of glucose and free fatty acids will also trigger the rerouting of FAs and glucose to alternative pathways accumulating products that add to the cellular stress. Lastly, ectopic fat forms as well as glycosylated proteins. Both contribute to cellular stress as well.

Increased cellular strees sends the cell into a vicous cycle. Mitochondria function only at reduced capacity and ATP production declines. Addected individuals will tire out fast, immune system and other metabolic functions decline. ER stress will lead to increased accumulation of cellular garbage and cellular signalling leads to increased cell death (apoptosis).

In consequence systemic inflammation increases speeding up the risk for T2D, CVD, non-alcoholic fatty liver disease, reduced cognitive functioning. In short all body systems are affected.

Genetic Predisposition and Lifestyle Choices Interact to Accelerate or Slow Aging

Inflammaging looks more dramatic than it is. In healthy active adults and seniors these processes are ongoing, but 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 healthy lifestyle with lots of physical activity, a plant-based diet, and a positive, relaxed life seems to stem the tide.

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

As you have learned in module 1 most chronic diseases such as T2D and CVD, but also cancer, develop when a genetic predisposition meets increased chronic systemic inflammation due to obesity and an unhealthy lifestyle. If chronic systemic inflammation is already ongoing it adds to cellular aging and aggravates physiological inflammaging. The  aging process and the 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 and we know that developing chronic diseases can speed up aging tremendously. So, the question is how is aging sped up? One explanation is chronic systemic inflammation and 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 increase methylation so less desirable phenotypes such as T2D can be suppressed.

Phytochemicals from vegetables, soy, tea, and fruits as well as fiber intake via gut microbiome influence the epigenetic machinery positively. Exercising also changes epigenetic marks in a positive way.

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 acceleration or slow-down of the aging process. Scientists are 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 overall goal of the research in this area is to add as many healthy years to peoples’ lives.

The Key to Longevity? Dodging Chronic Diseases And Cognitive Decline

This closes the circle bringing  us back to the paradigm of this course. The key to a long and healthy life is avoiding chronic diseases as long as genetically possible.

As you have seen throughout this semester the prevention of chronic diseases begins before birth and depends on the health behavior of the mother during pregnancy. This process continues after birth when a healthy metabolism is set by the feeding decisions parents are making and the health behaviors that are 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.

This makes it clear that aging progresses vary individually. Therefore health care professionals should never assume but treat the heterogenous group of seniors on an individual basis.