Immune aging and how to combat it


With age, the human immune system becomes less effective at tackling infections and less responsive to vaccinations. At the same time, the aging immune system is associated with chronic inflammation, which increases the risk of almost all conditions linked to old age.

The good news is that exercising and adopting the right diet may help a person maintain healthy immunity into older age.

Chimpanzees and gorillas, our closest primate relatives, live for only 10–15 years in the wild once they have reached maturity. After the human evolutionary lineage split from theirs, our ancestors’ life expectancy doubled over the next 5 million years.

Scientists believe that it remained relatively stable into the 18th century. In the 250 years between then and now, however, life expectancy more than doubled again due to improvements in sanitation and healthcare.

We live in a time of high average life expectancies. However, our long evolutionary history has adapted us for different lifestyles (and even life expectancies), and these have changed drastically.

As a result, immunity not only weakens in older age; it also becomes imbalanced. This affects the two branches of the immune system — “innate” immunity and “adaptive” immunity — in a double whammy of “immunosenescence.”

“Innate” immunity, which is our first line of defense against infections, fails to resolve after the initial threat has passed, causing chronic, systemic inflammation.

“Adaptive” immunity, which is responsible for remembering and attacking particular pathogens, steadily loses its ability to defend against viruses, bacteria, and fungi.

Chronic, low-grade inflammation is associated with almost all conditions linked to older age, including type 2 diabetes, cardiovascular disease, cancer, and dementia. It also plays a leading role in certain autoimmune conditions that are more common in older adults, such as rheumatoid arthritis.

Meanwhile, the loss of adaptive immunity that comes with older age not only makes people more susceptible to infections; it can also reactivate dormant pathogens that were previously suppressed.

In addition, the weaker adaptive immunity of older adults means that their bodies respond less strongly to vaccinations, such as the annual flu shot.

Aging and innate immunity

Researchers have dubbed the persistent, low-level inflammation that is implicated in almost all conditions associated with older age as “inflammaging.”

“While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive.”

After an initial infection or injury, younger people’s immune systems switch to an anti-inflammatory response. This does not appear to happen as effectively in older adults. This is due to the accumulation of aged, or “senescent,” immune cells.

Senescent cells have shorter telomeres, which are the protective caps at the tips of chromosomes. Just as the plastic caps on the ends of shoelaces prevent them from fraying, telomeres prevent vital genetic material from becoming lost when the chromosome is copied during cell replication.

Telomeres get a little shorter every time a cell divides, until, eventually, division has to stop completely. If the cell survives, it becomes steadily more dysfunctional.

Senescent immune cells produce more immune signaling molecules called cytokines, which promote inflammation. Specifically, they churn out more interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha).

Scientists have linked high levels of IL-6 and TNF-alpha to disability and mortality in older adults. They have a particularly strong association with type 2 diabetes, cardiovascular disease, neurodegenerative disease, and cancer.

As the number of pro-inflammatory cells increases, there is an increase in the number of immune cells called M1 macrophages (more pro-inflammatory) and a decrease in the number of M2 macrophages (more immunoregulatory).

These changes in the frequency of M1 and M2 cells seem to be associated with an increased risk of developing plaques comprising fat and debris, which block the arteries in atherosclerosis.

Aging and adaptive immunity

Through adaptive immunity, the immune system learns to recognize and neutralize particular pathogens.

A type of immune cell known as a T cell plays a crucial role in adaptive immunity. In the course of an infection, “naïve” T cells learn to recognize the specific pathogen involved. They then differentiate into cells that are specialized to mount future immune responses against the same pathogen.

The total number of T cells remains constant throughout our lifetime, but the pool of naïve, undifferentiated cells steadily shrinks over the years, as more and more cells commit to tackling specific infections.

As a result, the bodies of older adults become less able to mount effective immune responses to new infections. For the same reason, vaccinations provoke weaker responses from the aging immune system and, therefore, provide less protection.

Ironically, a lifetime of influenza vaccinations may, in itself, diminish the efficacy of the annual vaccine later in life. Indeed, research suggests that repeated influenza immunizations could lead to reduced antibody responses.

Many older adults harbor a latent infection of human cytomegalovirus. This viral infection is very common and persistent, and it usually produces few (if any) symptoms. However, in older adults, this infection may steadily deplete their immune resources, making them more prone to other viral infections and reducing the effect of influenza immunizations.

In addition to this slow decline in immunity with age, senescent T cells also produce more pro-inflammatory cytokines, such as IL-6. These, in turn, stoke the chronic, systemic inflammation of inflammaging.

Holding back the years

Although nothing can prevent aging, there are certain lifestyle changes a person can make to stay healthy into older age.

The sections below will look at these factors in more detail.

Getting regular physical activity

Exercise has a profound effect on the immune system, according to a recent overview of research in the journal Nature Reviews Immunology.

Inevitably, people become less physically active as they age, but there is evidence to suggest that getting as much exercise as possible can slow or even reverse some of the effects of immunosenescence.

Skeletal muscle produces a range of proteins called myokines that reduce inflammation and preserve immune function. Therefore, it makes sense that maintaining muscle mass through exercise protects against infection and conditions such as type 2 diabetes and cardiovascular disease, which are closely linked to chronic inflammation.

One study found that aerobic fitness among 102 healthy males, aged 18–61 years, was inversely proportional to the number of senescent T cells in their blood after adjusting for age. In other words, increased physical fitness was associated with less immunosenescence.

The fittest males not only had fewer senescent T cells but a greater number of naïve T cells.

Another study compared the immune responses of 61 healthy males, aged 65–85 years, to a flu vaccination. Around one-third of the males were intensively active (though participation in running or sports), one-third were moderately active, and one-third were mostly inactive.

After adjusting for their age, the researchers found that the intensively and moderately active males produced more antibodies in response to vaccination than the least active males.

Remarkably, the more active males had higher serum concentrations of antibodies to some flu strains even before they underwent vaccination.

A range of other studies have identified similar benefits, not only from long-term physical activity but also from single bouts of exercise before vaccination.

“Taken together, these studies suggest that the emergence of certain features of immunosenescence and the extent of immune remodeling is likely to be heavily influenced by insufficient physical activity as humans age.”

It is important to note that the majority of the research into the relationship between exercise and immunity in older adults has involved “cross-sectional” studies. This type of study investigates relationships between variables at a single point in time.

To confirm the benefits of physical fitness, the authors of the review above call for more “interventional” studies, which would follow participants over time.

Adopting the Mediterranean diet

For now, there is no direct evidence to suggest that making dietary changes can slow the rate of immunosenescence in older adults. However, there is plenty of indirect evidence.

In particular, research suggests that diet helps determine older adults’ risk of developing sarcopenia. This condition causes a loss of muscle mass, strength, and functionality.

There appears to be a two-way relationship between skeletal muscle and the immune system. Muscles produce anti-inflammatory myokines, but recent evidence suggests that chronic inflammation also accelerates the muscle loss in sarcopenia.

Taking dietary supplements that reduce the risk of sarcopenia — such as vitamin D and polyunsaturated fatty acids — may help, due to their anti-inflammatory properties.

A growing body of evidence also suggests that people who eat a Mediterranean diet are less likely to become “frail” in older age, such as by losing muscle strength, walking slowly, and tiring easily.

The Mediterranean diet comprises:

  • large amounts of fruit, leafy vegetables, and olive oil
  • moderate amounts of fish, poultry, and dairy
  • low amounts of red meat and added sugar

Previous studies have linked this diet to a lower risk of obesity, cardiovascular disease, type 2 diabetes, and cancer.

A 2018 review of observational studies, which Medical News reported on, found that people who adhered the most closely to the Mediterranean diet were less than half as likely to become frail over a 4-year period, compared with those who followed it the least closely.

Among other possible explanations, this may be a result of the diet’s anti-inflammatory properties. The authors write:

“Frail individuals have higher levels of inflammatory markers, and inflammation is considered to be closely associated with frailty. A Mediterranean diet is associated with low levels of inflammatory markers and may reduce frailty risk through this mechanism.”

Maintaining a moderate weight

Although muscle plays a role in reducing inflammation in older adults, fat, or “adipose,” tissue may have the opposite effect.

Normal aging often leads to weight gain, due to an accumulation of adipose tissue beneath the skin and around the organs. According to a roundup of research on the aging immune system, adipose tissue may make a significant contribution to inflammaging.

Up to 30% of the pro-inflammatory cytokine IL-6 in the bloodstream may originate from adipose tissue. Therefore, having obesity or overweight in older age may significantly contribute to chronic inflammation.

In addition, animal and human studies suggest that the immune system of people with obesity may produce fewer antibodies in response to the flu vaccination.

Exercising and eating a healthful diet appear to counter the effects of immune aging. In part, this might be due to the way that these two lifestyle factors prevent excessive weight gain.

Studies have suggested that older adults who exercise regularly and have a moderate weight have fewer senescent T cells and lower levels of pro-inflammatory cytokines in their blood.

However, whether or not diet, exercise, and weight loss can reverse immunosenescence remains an open question for future research.

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