The SCI state in older individuals is thought to be caused in part by a complex process called cellular senescence, which is characterized by an arrest of cell proliferation and the development of a multifaceted senescence-associated secretory phenotype (SASP)53. A prominent feature of this phenotype is increased secretion of pro-inflammatory cytokines, chemokines and other pro-inflammatory molecules from cells53. Senescent cells expressing this phenotype can in turn promote a multitude of chronic health conditions and diseases, including insulin resistance, CVD, pulmonary arterial hypertension, chronic obstructive pulmonary disorder, emphysema, Alzheimer’s and Parkinson’s diseases, macular degeneration, osteoarthritis and cancer54,55.

How senescent cells acquire the SASP is not fully understood, but existing research points to a combination of both endogenous and non-endogenous social, environmental and lifestyle risk factors. Among the known endogenous causes of this phenotype are DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals and oxidative stress56. The non-endogenous contributors are thought to include chronic infections57, lifestyle-induced obesity58, microbiome dysbiosis59, diet60, social and cultural changes61,62 and environmental and industrial toxicants63. The fact that differences exist in the extent to which older adults exhibit SCI52,64 is thought to be indicative of inter-individual differences in exposure to these and other related pro-inflammatory factors, although studies documenting within-person associations between these risk factors and SCI are limited.

Nevertheless, differences in non-communicable diseases associated with SCI are evident across cultures and countries. Most prominently, SCI-related disease rates have increased dramatically for both older and younger individuals living in industrialized countries who follow a Western lifestyle but are relatively rare among individuals in non-Westernized populations who adhere to diets, lifestyles and ecological niches that more closely resemble those present during most of human evolution65,66,67,68,69,70,71. Furthermore, dietary and lifestyle habits, as well as exposure to a variety of different pollutants, can increase oxidative stress, upregulate mitogenic signaling pathways and cause genomic and epigenomic perturbations8,60,62,63 that can induce the SASP. Further evidence for a role of lifestyle in the development of chronic inflammation comes from a study of 210 healthy twins between 8 and 82 years old, which found that non-heritable factors are the strongest contributors to differences in chronic inflammation across individuals72 and that exposure to environmental factors, which have been collectively called the exposome, are the main drivers of SCI. Simply put, the exposome refers to a person’s lifelong exposure to physical, chemical and biological elements, starting from the prenatal period onward73.

Chronic infections

The effect of lifelong infections caused by cytomegalovirus, Epstein–Barr virus, hepatitis C virus and other infectious agents on SCI and immune dysregulation remains controversial74,75,76,77,78. In terms of aging, chronic infection with cytomegalovirus has been associated with the so-called immune risk phenotype that has been predictive of early mortality in several longitudinal studies79. Furthermore, chronic infection with HIV causes premature aging of the immune system and is associated with early cardiovascular and skeletal changes57, with such effects being attributed in large part to the accumulation of senescent CD8+ T cells that produce increased levels of pro-inflammatory mediators80.

Although several studies have reported associations between chronic infections and autoimmune diseases, certain cancers, neurodegenerative diseases and CVD, chronic infections appear to interact synergistically with environmental and genetic factors to influence these health outcomes76,77,81. Indeed, humans coevolved with a variety of viruses, bacteria and other microbes82, and while chronic infections appear to contribute to SCI, they are not likely the primary driver. For instance, populations of hunter-gatherers and other existing non-industrialized societies such as the Shuar hunter-gatherers of the Ecuadorian Amazon83,84, Tsimané forager-horticulturalists of Bolivia68, Hadza hunter-gatherers from Tanzania67, subsistence agriculturalists from rural Ghana85 and traditional horticulturalists of Kitava (Papua New Guinea)86—all of whom are minimally exposed to industrialized environments but highly exposed to a variety of microbes—exhibit very low rates of inflammation-related chronic disease and substantial fluctuations in inflammatory markers that do not increase with age65,67,68,83,86.

Lifestyle, social and physical environment

Individuals in the populations mentioned above have relatively short life expectancies on average, which means that some die before showing signs of advanced aging. However, the relative absence of SCI-related health problems in these populations has not been attributed to genetics or to having a shorter life expectancy, but rather to lifestyle factors and the social and physical environments the people inhabit66. Their lifestyles, for example, are characterized by higher levels of physical activity67,71,87, diets composed mainly of fresh or minimally processed food sources66,88,89, and less exposure to environmental pollutants66. In addition, individuals living in these environments generally have circadian rhythms that are more closely synchronized with diurnal fluctuations in sunlight exposure90 and the social stressors they experience are different from those typically present in industrialized environments91.

These social and environmental characteristics are believed to have predominated during most of hominin evolutionary history until industrialization66,82,89. Industrialization conferred many benefits, including social stability; reduced physical trauma; access to modern medical technology; and improved public health measures, such as sanitation, quarantine policies and vaccination, all of which significantly decrease infant mortality rates and increase average life expectancy66. However, more recently, these changes also caused radical shifts in diet and lifestyle, resulting in living circumstances that are very different from the ones that shaped human physiology for most of evolution. This is believed to have created an evolutionary mismatch in humans—characterized by an increasing separation from their ecological niche—and this mismatch, in turn, has been hypothesized to be a major cause of SCI65,66,82,89,92.

Physical activity

Industrialization is thought to have caused a significant overall decrease in physical activity. One study showed that, worldwide, 31% of individuals are considered physically inactive—defined as not meeting the minimum international recommendations for regular physical activity—with levels of inactivity being higher in high-income countries than in low-to-middle-income countries93. In the United States, these numbers are even higher, with approximately 50% of American adults being considered physically inactive94.

Skeletal muscle is an endocrine organ that produces and releases cytokines and other small proteins, called myokines, into the bloodstream. This occurs particularly during muscle contraction and can have the effect of systemically reducing inflammation95. Low physical activity, therefore, has been found to be directly related to increased anabolic resistance96 and levels of CRP and pro-inflammatory cytokine levels in healthy individuals97, as well as in breast cancer survivors98 and patients with type 2 diabetes99. These effects can, in turn, promote several inflammation-related pathophysiologic alterations, including insulin resistance, dyslipidemia, endothelial dysfunction, high blood pressure and loss of muscle mass (sarcopenia)100, that have been found to increase risk for a variety of conditions, including CVD, type 2 diabetes, NAFLD, osteoporosis, various types of cancer, depression, dementia and Alzheimer’s disease, in individuals who are chronically inactive95,100.

Consistent with these effects, there is strong evidence for an association between physical inactivity and increased risk for age-related diseases and mortality. A recent meta-analysis of studies with cohorts from Europe, the United States and the rest of the world that included 1,683,693 participants found that going from physically inactive to achieving the recommended 150 minutes of moderate-intensity aerobic activity per week was associated with lower risk of CVD mortality by 23%, CVD incidence by 17%, and type 2 diabetes incidence by 26% during an average follow-up period of 12.8 years101. Moreover, data from 1.44 million participants across several prospective cohort studies revealed that, as compared to individuals exhibiting high levels of leisure-time physical activity (≥90th percentile), those who were physically inactive (≤10th percentile) had a greater risk (>20%) of developing several cancers, including esophageal adenocarcinoma; liver, lung, kidney, gastric cardia and endometrial cancers; and myeloid leukemia, even after adjusting for multiple major risk factors such as adiposity and smoking status (except for lung cancer)102. Likewise, a meta-analysis of ten studies and 23,345 older adults (70 to 80 years old) who were followed for 3.9–31 years found that individuals meeting the minimum international physical activity recommendations had a 40% lower risk of Alzheimer’s disease as compared to their physically inactive counterparts103.

Finally, physical inactivity can increase individuals’ risk for various non-communicable diseases because it is linked to obesity100 and, in particular, excessive visceral adipose tissue (VAT), which is a significant trigger of inflammation104,105,106. VAT is an active endocrine, immunological and metabolic organ composed of various cells (including immune cells, such as resident macrophages) that expands mostly through adipocyte hypertrophy, which can lead to areas of hypoxia and even cell death, resulting in activation of hypoxia-inducible factor-1α, increased production of reactive oxygen species, and release of DAMPs (for example, cell-free DNA). These events can induce the secretion of numerous pro-inflammatory molecules, including adipokines, cytokines (for example, IL-1β, IL-6, TNF-α), and chemokines (especially monocyte chemoattractant protein-1) by adipocytes, endothelial cells and resident adipose tissue immune cells (for example, macrophages)105,106,107,108. This in turn leads to the infiltration of various immune cells in the VAT, including monocytes, neutrophils, dendritic cells, B cells, T cells and NK lymphocytes, and a reduction in T regulatory cells, thereby amplifying inflammation, which can eventually become prolonged and systemic in some individuals106,107,108,109.

Furthermore, TNF-α and other molecules can cause adipocyte insulin resistance, which increases lipolysis, with the resulting spillover of lipids into other organs, such as the pancreas and liver, where they can contribute to beta-cell dysfunction, hepatic insulin resistance and fatty liver106. Hence, visceral obesity accelerates aging and increases risk for cardiometabolic, neurodegenerative and autoimmune diseases, as well as several types of cancer19,104,106,110,111,112. These dynamics are known to occur in adults and can promote age-related disease risk, but they first emerge during childhood26. The childhood obesity epidemic might thus be playing a key role in promoting inflammation and age-related disease risk worldwide113.

Microbiome dysbiosis

Obesity may also lead to SCI through gut microbiome-mediated mechanisms114. For example, studies conducted in moderately obese Danish individuals without diabetes115 and in severely obese French women116 found changes in gut microbiota composition and microbial gene richness that were correlated with increased fat mass, pro-inflammatory biomarkers and insulin resistance. Furthermore, in older adults, changes in the gut microbiota seem to influence the outcome of multiple inflammatory pathways59.

Obesity, which is strongly linked to changes in the gut microbiome, has also been associated with increased intestinal paracellular permeability and endotoxemia114,117. Moreover, the latter is a suspected cause of inflammation through activation of pattern recognition receptors, such as Toll-like receptors, in immune cells and of inflammation-mediated metabolic conditions such as insulin resistance118. Interestingly, serum concentrations of zonulin, a protein that increases intestinal permeability, appear to be elevated in obese children and adults117,119, and in persons with type 2 diabetes118, NAFLD, coronary heart disease, polycystic ovary syndrome, autoimmune diseases and cancer117. More recently, elevated serum zonulin concentrations have been found to predict inflammation and physical frailty120.

More broadly, it has been hypothesized that a complex balance exists in the intestinal ecosystem that, if disrupted, can compromise its function and integrity and in turn cause low-grade SCI59. It may thus be important to identify possible triggers of dysbiosis and intestinal hyperpermeability, which could potentially include the overuse of antibiotics, nonsteroidal anti-inflammatory drugs and proton-pump inhibitors121,122; lack of microbial exposure induced by excessive hygiene and reduced contact with animals and natural soils, which is a very recent phenomenon in human evolutionary history82,123; and diet123 (see below).

Diet

The typical diet that has become widely adopted in many countries over the past 40 years is relatively low in fruits, vegetables and other fiber- and prebiotic-rich foods66,123,124,125 and high in refined grains124, alcohol126 and ultra-processed foods125, particularly those containing emulsifiers127. These dietary factors can alter the gut microbiota composition and function123,127,128,129,130 and are linked to increased intestinal permeability129,130,131 and epigenetic changes in the immune system129 that ultimately cause low-grade endotoxemia and SCI129,130,131. The influence of diet on inflammation is not confined to these effects, though. For example, orally absorbed advanced glycation and lipoxidation end-products that are formed during the processing of foods or when foods are cooked at high temperatures and in low-humidity conditions are appetite increasing and are linked to overnutrition and hence obesity and inflammation132. Furthermore, high-glycemic-load foods, such as isolated sugars and refined grains, which are common ingredients in most ultra-processed foods, can cause increased oxidative stress that activates inflammatory genes133.

Other dietary components that are thought to influence inflammation include trans fatty acids134 and dietary salt. For example, salt has been shown to skew macrophages toward a pro-inflammatory phenotype characterized by the increased differentiation of naive CD4+ T cells into T helper (T H )-17 cells, which are highly inflammatory, and decreased expression and anti-inflammatory activity of T regulatory cells135. In addition, high salt intake can cause adverse changes in gut microbiota composition, as exemplified by the reduced Lactobacillus population observed in animals and humans fed high-salt diets135. This specific population is critical for health as it regulates T H 17 cells and enhances the integrity of the intestinal epithelial barrier, thus reducing systemic inflammation135. Consistent with the expected health-damaging effects of consuming foods that are high in trans fats and salt, a recent cohort study of 44,551 French adults who were followed for a median of 7.1 years found that a 10% increase in the proportion of ultra-processed food consumption was associated with a 14% greater risk of all-cause mortality136.

Several other nutritional factors can also promote inflammation and potentially contribute to the development of SCI. These factors include deficiencies in micronutrients, including zinc137 and magnesium138, which are caused by eating processed or refined foods that are low in vitamins and minerals, and having suboptimal omega-3 levels139, which impacts the resolution phase of inflammation. Long-chain omega-3 fatty acids—especially eicosapentaenoic acid and docosahexaenoic acid—modulate the expression of genes involved in metabolism and inflammation139. More importantly, they are precursors to molecules such as resolvins, maresins and protectins that are involved in the resolution of inflammation28,29. The main contributors to the growing worldwide incidence of low omega-3 status are a low intake of fish and high intake of vegetable oils that are high in linoleic acid, which displaces omega-3 fatty acids in cell membrane phospholipids140,141. In turn, various RCTs have shown that omega-3 fatty acid supplementation reduces inflammation142,143,144 and may thus have health-promoting effects141,142,143,144.

Evidence linking diet and mortality is robust. For example, an analysis of nationally representative health surveys and disease-specific mortality statistics from the National Center for Health Statistics in the United States showed that the dietary risk factors associated with the greatest mortality among American adults in 2005 were high dietary trans fatty acids, low dietary omega-3 fatty acids, and high dietary salt145. In addition, a recent systematic analysis of dietary data from 195 different countries identified poor diet as the main risk factor for death in 2017, with excessive sodium intake being responsible for more than half of diet-related deaths146.

Finally, when combined with low physical activity, consuming hyperpalatable processed foods that are high in fat, sugar, salt and flavor additives147 can cause major changes in cell metabolism and lead to the increased production (and defective disposal) of dysfunctional organelles such as mitochondria, as well as to misplaced, misfolded and oxidized endogenous molecules30,60,148. These altered molecules, which increase with age19,30, can be recognized as DAMPs by innate immune cells, which in turn activate the inflammasome machinery, amplify the inflammatory response1,30,60 and contribute to a biological state that has been called “inflammaging,” defined as the “the long-term result of the chronic physiological stimulation of the innate immune system” that occurs in later life30. As proposed, inflammaging involves changes in numerous organ systems, such as the brain, gut, liver, kidney, adipose tissue and muscle19, and it is driven by a variety of molecular-age-related mechanisms that have been called the “Seven Pillars of Aging”55—namely, adaptation to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis and stem cells and regeneration.

Social and cultural changes

In addition to physical inactivity and diet, the industrial revolution and modern era have ushered in changes in social interactions and sleep quality59,91 that can promote SCI149,150 and insulin resistance151, in turn increasing risk for obesity, type 2 diabetes, CVD and all-cause mortality150,151,152,153,154. Moreover, psychological stressors that are persistently present in some contemporary work environments, such as those characterized by high job demand and low control, can cause physiologic changes155 that disrupt the ability for glucocorticoids to effectively down-regulate inflammatory activity due to decreased sensitivity caused by chronic elevation in cortisol, leading in turn to SCI and poor health156.

Another core feature of modern society that has occurred very recently in human evolutionary history is increased exposure to artificial light, especially the blue spectrum, at atypical biologic times157,158,159. Exposure to blue light, especially after sundown, increases arousal and alertness at night and thus causes circadian rhythm disruption158,159, which in turn promotes inflammation160, and is a risk for multiple inflammation-related diseases157,159. As an example, night-shift work has been found to increase risk for the metabolic syndrome and is suspected of being a causal factor in obesity, type 2 diabetes and CVD, as well as in breast, ovarian, prostate, colorectal and pancreatic cancer157.

Environmental and industrial toxicants

The rapid rise in urbanization over the past 200 years8 brought with it an unprecedented increase in humans’ exposure to various xenobiotics, including air pollutants, hazardous waste products and industrial chemicals that promote SCI8,161. Each year, an estimated 2,000 new chemicals are introduced into items that individuals use or ingest daily, including foods, personal care products, prescription drugs, household cleaners and lawn care products (see https://ntp.niehs.nih.gov). The concomitant increase in the estimated contribution of environmental chemicals to human disease burden162 has prompted a shift toward data generation using high-throughput screening to investigate the effect of industrial toxicants on cellular pathways, which has been supported by initiatives like the US Federal Tox21 Program, and toward the adoption of translational systems-toxicology approaches for integrating diverse data streams to better understand how chemicals affect human health and disease outcomes163. The Tox21 Program has tested more than 9,000 chemicals using more than 1,600 assays and has demonstrated that numerous chemicals to which people are commonly exposed greatly alter molecular signaling pathways that underlie inflammation and inflammation-related disease risk164. These chemicals include phthalates, per- and polyfluoroalkyl substances, bisphenols, polycyclic aromatic hydrocarbons and flame retardants165.

These compounds and others promote inflammatory activity via multiple mechanisms. For example, they can be cytotoxic8,162, cause oxidative stress or act as endocrine disruptors, starting in utero8. These chemicals are thus suspected of playing a causal role in hormone-dependent cancers, metabolic syndrome, type 2 diabetes, hypertension, CVD, allergy and asthma, and autoimmune and neurodegenerative diseases8,162,166. Tobacco smoking, which remains a worldwide health problem, is yet another source of xenobiotics that has been associated with a variety of inflammation-related diseases167.