Aging is a universal rite of passage and an inevitable consequence of existence. Numerous theories have been proposed to understand aging at the cellular level.

 

Theories of aging

 

One prominent theory, the oxidative damage theory, suggests that our body's pro-oxidant/antioxidant equilibrium tilts toward pro-oxidants as we age.

Aging: The Biology of Senescence. Chapter 18. In: Gilbert SF. Developmental Biology. 6th edition. Sunderland, MA: Sinauer Associates; 2000.

The over-accumulation of reactive oxygen species wreaks havoc on cell membranes, nucleic acids, and proteins, ultimately leading to senescence.

 

Another theory, known as the "wear-and-tear" theory, attributes aging to accumulated traumas, telomere shortening, mutations, mitochondrial genome damage, and enzyme inefficiencies within the body.

 

 

Inflammation and aging

 

In 2000, Claudio Franceschi and colleagues introduced the concept of inflammaging, which transformed our understanding of aging and the immune system.

Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–254.

In a 2023 review of the immunology of aging, Franceschi writes that, as individuals age, there is a decline in adaptive immunity, known as “immunosenescence.”

Fulop T, Larbi A, Pawelec G, et al. Immunology of Aging: the Birth of Inflammaging. Clin Rev Allergy Immunol. 2023;64(2):109–122.

This is coupled with an activation of innate immunity and increased pro-inflammatory activity, termed inflammaging.

 

 

European researchers publishing in Cell have identified nine hallmarks of aging, which include genome instability, epigenetic changes, telomere shortening, mitochondrial dysfunction, dysregulation of nutrient-sensing mechanisms, loss of proteostasis, cellular senescence, depletion of stem cells, and altered intercellular communication.

López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153(6):1194–1217.

In their 2023 review, Franceschi and colleagues consider inflammaging to be related to the hallmark of altered intercellular communication. 

 

 

Catalysts of inflammaging

 

The theory of inflammaging has undergone significant evolution since its inception more than 2 decades ago. The most common contributors are listed below.

Immunosenescence 

According to an article in Lifespan.io, an aging immune system leads to inappropriate immune responses, higher susceptibility to infections, autoimmune reactions, cancer, and reduced response to vaccinations and wound healing. Chronic inflammatory diseases and persistent infections like CMV, HIV, and Epstein–Barr virus can worsen immunosenescence, connecting it to microbial burden.

What is Inflammaging? Chronic Inflammation and Aging. Lifespan.io. February 28, 2022.

 

Innate immunity

According to Franceschi’s 2000 article, the innate immune system's three primary functions are preventing and mitigating damage, priming the adaptive immune system, and facilitating antigen presentation. But aging alters these functions. Phagocytic innate immune cells, such as macrophages, monocytes, and NK cells, undergo phenotypic alterations and reduced functionality with advancing age. 

Innate immune cells in older individuals remain chronically activated, producing higher pro-inflammatory mediators, such as free radicals and pro-inflammatory cytokines, without mounting a protective immunity.

Adaptive immunity

Aging reduces naive T cells and increases memory T cells. Thymic involution, Franceschi proposed, is a primary cause of this decline. This leads to increased vulnerability to infections, cancer, and reduced vaccine efficacy in older individuals. Aging T cells release pro-inflammatory factors, contributing to chronic inflammation. Changes in cell membranes and impaired signaling pathways further affect T cell functions and metabolism. 

 

The “two hits” theory

 

Franceschi and colleagues attribute an individual's susceptibility to age-related diseases to their genetic makeup and response to stressors. Variation in genetic backgrounds, however, makes it challenging to predict aging rates at an individual level.

Senescent cells 

Senescent (or nondividing) cells release inflammatory cytokines through the senescence-associated secretory phenotype, according to the authors of the Lifespan.io article. The decline in the immune system's ability to remove senescent cells creates a feedback loop that intensifies inflammation. 

Cell debris

Improper cell destruction during aging generates cell debris, such as damaged organelles and cells, as well as damage-associated molecular patterns, which trigger innate immunity and promote persistent inflammation. 

Microbial burden

The integrity of oral and gut mucosa barriers declines with age, allowing harmful bacteria, such as Streptococcus spp., Staphylococcus spp., Enterococcus spp., and Enterobacter spp. to proliferate. This imbalance and a decline in beneficial bacteria such as Bifidobacterium spp. and Faecalibacterium prausnitzii increase inflammation. 

 

Can you “bio-hack” inflammaging?

 

There are myriad ways to offset inflammaging and its effects, including the following: 

• Senolytics: Novel drugs called senolytics, including dasatinib, quercetin, and UBX1325, have shown promising results in preclinical studies for eliminating senescent cells and reducing inflammation.

  What Are Senolytics? Senotherapeutics for Senescent Cells. Lifespan.io. March 29, 2022.

  Researchers are investigating their efficacy in treating osteoarthritis, atherosclerosis, and diabetic macular edema. 

   

• Exercise: A study published in the Journal of Applied Physiology revealed that older men who consistently engaged in regular aerobic exercise had a higher chance of delaying or preventing inflammaging.

  Lavin KM, Perkins RK, Jemiolo B, et al. Effects of aging and lifelong aerobic exercise on basal and exercise-induced inflammation. J Appl Physiol. 2020;128(1):87–99.

   

• Mediterranean Diet: This type of diet offers potential benefits in reducing inflammaging, as it contains phytochemicals such as ferulic acid, resveratrol, phenethyl isothiocyanate, and luteolin, which act as nutritional hormetins.

  Martucci M, Ostan R, Biondi F, et al. Mediterranean diet and inflammaging within the hormesis paradigm. Nutr Rev. 2017;75(6):442–455.

  The Mediterranean diet emphasizes veggies, whole grains, and healthy fats.