Age is a key factor in effective immune response

Long life is bad for health and survival, explained Cornelia M. Weyand, MD, PhD, Professor of Medicine and Immunology at Mayo Alix School of Medicine and Stanford School of Medicine, during ACR Convergence 2021.

“Of all the things we do in life, aging is one of the most dangerous,” she said. “After about the age of 45, there is increasing risk of developing age-related morbidities. This risk accelerates after about the age of 60 for most people.”

For even the healthiest humans, the age-related risk of cancer, cardiovascular disease, infectious disease, and neurodegenerative disease comes back to one factor: older immune systems are less flexible, less responsive, and less effective.

“The immune system is restructured with age,” Dr. Weyand said. “The immune system of a 60-year-old looks very different from the immune system of a 20-year-old. You need to keep that in mind when you treat patients.”

Dr. Weyand explored the mechanisms and sequelae of aging immune systems during Immune Responses in the Elderly. The session, which was presented on Monday, Nov. 8, can be viewed by registered meeting participants through March 11, 2022.

Immune aging begins around age 20 and accelerates around 50, Dr. Weyand said. It is also species-specific.

“What we learn in other species, say mice, does not necessarily relate to humans,” she noted.

In humans, aging-related morbidities emerge at different stages and progress differently over the years. Cancer incidence, for example, rises sharply starting around age 45, peaks around 85, and declines thereafter. Cardiovascular disease likewise begins to climb around 45, but the incidence continues to climb steadily. Infectious disease incidence begins climbing in the mid-50s and accelerates with age, while neurodegenerative diseases tend to emerge later, around age 70, and increase at a steady rate. Chemotherapy, chronic infection, and other events can contribute to premature immune aging.

Immunosenescence results in loss-of-function in protective immunity, reducing protection against infection and malignancy, decreasing the effectiveness of vaccines, and slowing wound healing. Immunosenescence also results in gain-of-function for inflammation, a process dubbed “inflammaging,” resulting in increased incidence of autoimmune, neurodegenerative, and cardiovascular disease.

Immunosenescence begins with myeloid skewing in the bone marrow with less self-renewal and more cellular damage, Dr. Weyand explained. Naïve lymphocyte output decreases as adiposity in the thymus and bone marrow increases and more inflammatory cytokines are produced, altering lymphocyte function.

The naïve lymphocyte pool shrinks, resulting in more cells with unconventional phenotype and function that produce more inflammatory and profibrotic cytokines. Skin, gut, and lung tissues become less supportive to robust immune function. Insufficient replenishment of long-lived lymphocytes and proliferative pressure lead to a decline in immunity.

The age-related decline in anti-viral immunity is a familiar problem. Failing immunity can lead to the familiar reactivation of varicella-zoster virus, resulting in shingles. Declining immune function is even more important in SARS-CoV-2, a novel human pathogen.

Case fatality rates are strongly associated with age, rising from near-zero in children to 0.4-1% in middle age to 13-20% at age 80 and older. The global case fatality is about 2%, Dr. Weyand noted, and 1.7% in the United States.

“Our patients are even more likely to die,” she said. “In a mixed-age global cohort of patients with rheumatic disease, case fatality was 5.5%. That is similar to case-fatality rates for people with cancer diagnosed with COVID-19.”