Chronic inflammation and the hallmarks of aging

Baechle, Jordan J.; Chen, Nan; Makhijani, Priya; Winer, Shawn; Furman, David; Winer, Daniel A.

doi:10.1016/j.molmet.2023.101755

Cited by 98 publications

(23 citation statements)

References 421 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When conducting translational studies on KD feeding, it may be important to prevent obesity and metabolic maladaptation, and to take sufficient breaks during a long-term dietary intervention. Our study shows that sporadic KD feeding could serve as a feasible dietary intervention for human aging by preventing chronic inflammation, a hallmark of aging 33,77 .…”

Section: Discussionmentioning

confidence: 77%

“…Goldberg et al found that a one-week KD activates γδ T cells in adipose tissue and restricts inflammation, whereas a four-month ad libitum KD promotes obesity and adipose chronic inflammation in mice 31 , which suggests the effects of a KD in chronic inflammation depend on the feeding regimens (e.g., durations, obesogenic / non-obesogenic). Chronic inflammation is a hallmark of aging and is associated with morbidity and mortality in aging 14,32,33 . We hypothesized a KD inhibits chronic inflammation during aging (“inflammaging”) if the KD does not cause obesity.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Nomura,

Murad,

Madhavan

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionallyin vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB’s anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demon-strate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Nomura,

Murad,

Madhavan

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, the analysis of mitochondrial respiratory chain enzymes indicates disturbances in the activities of Complex I-V in the elderly group, providing insights into the functional consequences of mitochondrial dysfunction. Variations in mitomiR expression profiling, which showed differences in mitomiR levels between the two groups and highlighted the function of these short RNAs in controlling the expression of mitochondrial genes and epigenetic modifications in mtDNA [33]. Upon further assessment group II was also found to be associated with more post-translational histone modifications.…”

Section: Discussionmentioning

confidence: 99%

Molecular insights into mitoepigenetic stress response signaling in age-associated cardiovascular disease risk

Soni,

Kaur,

Gurjar

et al. 2024

Preprint

View full text Add to dashboard Cite

Cardiovascular diseases (CVD) represent a major challenge for the elderly population and continue to be among the leading causes of mortality worldwide. The integrity of mitochondria in peripheral lymphocytes can indicate age-related degenerative disorders, revealing the balance between bioenergetics, inflammation, and senescence. The present study aims to investigate the impact of aging on mitochondrial-mediated epigenetic stress response mechanisms in both young and elderly individuals. Mitochondrial oxidative DNA damage, repair response, copy number, methylation, fusion, fission genes, electron transport chain enzyme complex activities, pro-inflammatory cytokine levels, and associated epigenetic mechanisms were evaluated. The results demonstrate that the elderly group experienced more significant disruption in the expression of mitochondrial genes, leading to impaired mitochondrial DNA (mtDNA) integrity closely linked to mitochondrial-nuclear crosstalk, ultimately increasing their susceptibility to CVD. The findings highlight mitochondria's crucial role in cellular dynamics, influencing stress responses and epigenetic mechanisms through fusion and fission cycles. Overall, these insights provide valuable information about the complex molecular processes linking mitochondrial dysfunction to age-related cardiovascular risks, paving the way for further exploration and potential interventions in aging-related health outcomes.

show abstract

“…Inflammaging, a hallmark of an aging immune system, is characterized by a persistent low-grade inflammation that increases the risk for age-related diseases [1][2][3] . Macrophages and monocytes play a crucial role in identifying cellular stress as stimuli, leading to sustained chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Inflammaging and fatty acid oxidation in monocytes and macrophages

Kruglov,

Jang,

Camell

2024

Immunometabolism

View full text Add to dashboard Cite

Fatty acid oxidation (FAO), primarily known as β-oxidation, plays a crucial role in breaking down fatty acids within mitochondria and peroxisomes to produce cellular energy and preventing metabolic dysfunction. Myeloid cells, including macrophages, microglia, and monocytes, rely on FAO to perform essential cellular functions and uphold tissue homeostasis. As individuals age, these cells show signs of inflammaging, a condition that includes a chronic onset of low-grade inflammation and a decline in metabolic function. These lead to changes in fatty acid metabolism and a decline in FAO pathways. Recent studies have shed light on metabolic shifts occurring in macrophages and monocytes during aging, correlating with an altered tissue environment and the onset of inflammaging. This review aims to provide insights into the connection of inflammatory pathways and altered FAO in macrophages and monocytes from older organisms. We describe a model in which there is an extended activation of receptor for advanced glycation end products, nuclear factor-κB (NF-κB) and the nod-like receptor family pyrin domain containing 3 inflammasome within macrophages and monocytes. This leads to an increased level of glycolysis, and also promotes pro-inflammatory cytokine production and signaling. As a result, FAO-related enzymes such as 5′ AMP-activated protein kinase and peroxisome proliferator-activated receptor-α are reduced, adding to the escalation of inflammation, accumulation of lipids, and heightened cellular stress. We examine the existing body of literature focused on changes in FAO signaling within macrophages and monocytes and their contribution to the process of inflammaging.

show abstract

Chronic inflammation and the hallmarks of aging

Cited by 98 publications

References 421 publications

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Molecular insights into mitoepigenetic stress response signaling in age-associated cardiovascular disease risk

Inflammaging and fatty acid oxidation in monocytes and macrophages

Contact Info

Product

Resources

About