Age-related Pathologies Research Articles

Age-Related Pathologies and Life Span

Both from a healthcare and a socioeconomic perspective, research on senescence is increasingly essential. Indeed, in industrialized countries, the increased human longevity confronts medicine with many old patients with age-related pathologies. The paper reviews the biological theories on aging, the impact of reactive oxygen species, telomers, epigenetics, and genetics (e.g., gerontogenes) on-age-related pathologies. Also, the paper reviews available and under research therapeutic approaches (e.g., senolytics) aimed to prolong life span and reduce the morbidity related to old age.

Stem cells from human exfoliated deciduous teeth rejuvenate the liver in naturally aged mice by improving ribosomal and mitochondrial proteins

Background aimsAging is accompanied by a decline in cellular proteome homeostasis, mitochondrial, and metabolic function. Mesenchymal stromal cell (MSC) therapies have been reported to extend lifespan and delay some age-related pathologies, yet the anti-aging rate and mechanisms remain unclear. Here, we investigated the effects and mechanism by transplantation of stem cells from human exfoliated deciduous teeth (SHED) into the naturally aged mice model. MethodsSHED were cultured in vitro and injected into mice by caudal vein. The in vivo imaging uncovered that SHED labeled by DiR dye mainly migrated to the liver, spleen, and lung organs of wild-type mice. As the main metabolic organ and SHED homing place, the liver was selected for proteomics and aging clock algorithm (LiverClock) analysis, which was constructed to estimate the proteomic pattern related to liver age state. ResultsAfter 6 months of continuous SHED injections, the liver proteomic pattern was reversed from senescent (∼30 months) to a youthful state (∼3 months), accompanied with upregulation of hepatocytes marker genes, anti-aging protein Klotho, a global improvement of liver functional pathways proteins, and a dramatic regulation of ribosomal and mitochondrial proteins, including upregulation of translation elongation and ribosome-sparing proteins Rpsa and Rplp0; elongation factors Eif4a1, Eef1b2, Eif5a; protein-folding chaperones Hsp90aa and Hspe1; ATP synthesis proteins Atp5b, Atp5o, Atp5j; and downregulation of most ribosomal proteins, suggesting that the proteome homeostasis destruction and mitochondria dysfunction in the aged mice liver might be relieved after SHED treatment. ConclusionsSHED treatment could dramatically relieve the senescent state of the aged liver, affect ribosome component proteins and upregulate the ribosomal biogenesis proteins in the aged mice liver. These results may help understand the improvements and mechanisms of SHED treatment in anti-aging.

Biomarkers of cellular senescence and risk of death in humans.

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

Combinatorial interventions in aging.

Insight on the underlying mechanisms of aging will advance our ability to extend healthspan, treat age-related pathology and improve quality of life. Multiple genetic and pharmacological manipulations extend longevity in different species, yet monotherapy may be relatively inefficient, and we have limited data on the effect of combined interventions. Here we summarize interactions between age-related pathways and discuss strategies to simultaneously retard these in different organisms. In some cases, combined manipulations additively increase their impact on common hallmarks of aging and lifespan, suggesting they quantitatively participate within the same pathway. In other cases, interactions affect different hallmarks, suggesting their joint manipulation may independently maximize their effects on lifespan and healthy aging. While most interaction studies have been conducted with invertebrates and show varying levels of translatability, the conservation of pro-longevity pathways offers an opportunity to identify 'druggable' targets relevant to multiple human age-associated pathologies.

The untapped potential of targeting NRF2 in neurodegenerative disease.

Since its initial discovery almost three decades ago, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has been shown to regulate a host of downstream transcriptional responses and play a critical role in preventing or promoting disease progression depending on the context. Critically, while the importance of proper nuclear factor erythroid 2-related factor 2 function has been demonstrated across a variety of pathological settings, the ability to progress NRF2-targeted therapeutics to clinic has remained frustratingly elusive. This is particularly true in the case of age-related pathologies, where nuclear factor erythroid 2-related factor 2 is a well-established mitigator of many of the observed pathogenic effects, yet options to target this pathway remain limited. Along these lines, loss of nuclear factor erythroid 2-related factor 2 function has clearly been shown to enhance neuropathological outcomes, with enhancing nuclear factor erythroid 2-related factor 2 pathway activation to prevent neurodegenerative/neurological disease progression continuing to be an active area of interest. One critical obstacle in generating successful therapeutics for brain-related pathologies is the ability of the compound to cross the blood brain barrier (BBB), which has also hampered the implementation of several promising nuclear factor erythroid 2-related factor 2 inducers. Another limitation is that many nuclear factor erythroid 2-related factor 2 activators have undesirable off-target effects due to their electrophilic nature. Despite these constraints, the field has continued to evolve, and several viable means of targeting nuclear factor erythroid 2-related factor 2 in a neuropathological context have emerged. In this perspective, we will briefly discuss the key findings and promising therapeutic options that have been discovered to date, as well as highlight emerging areas of NRF2-neurodegeneration research that provide hope for successfully targeting this pathway in the future.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease.

Cellular senescence is characteristic of the development and progression of multiple age-associated diseases. Accumulation of senescent cells in the heart contributes to various age-related pathologies. Several compounds called senolytics have been designed to eliminate these cells within the tissues. In recent years, the use and study of senolytics increased, representing a promising field for finding accessible and safe therapies for cardiovascular disease (CVD) treatment. This mini-review discusses the changes in the aging heart and the participation of senescent cells in CVD, as well as the use of senolytics to prevent the progression of myocardial damage, mainly the effect of dasatinib and quercetin. In particular, the mechanisms and physiological effects of senolytics therapies in the aged heart are discussed.

Hardware Plasmapheresis Use for Correction of Aging Biomarkers in Healthy Patients Aged 40–60 Years: an Original Study

INTRODUCTION. Due to the demographic aging of the population, the problem of treatment of age-related diseases and prevention of premature aging in modern healthcare has become particularly urgent. One of the most promising approaches is the impact on the molecular mechanisms of aging, including the activation of adaptive systems and suppression of pathological processes in the body. Methods of extracorporeal hemocorrection have proved to be a good idea in this respect.&#x0D; AIM. To evaluate the effectiveness and safety of hardware plasmapheresis as a technology for correcting aging biomarkers.&#x0D; MATERIAL AND METHODS. A technique of therapeutic plasmapheresis use was introduced for the correction of aging biomarkers. Twenty-four participants (male and female) aged 4060 years with an elevated level of one or more aging biomarkers underwent a course of therapeutic plasmapheresis in the daytime hospital. All participants underwent four procedures of therapeutic hardware plasmapheresis once every 3 days with 30 % volume of circulating plasma followed by replacement with colloid (5 % albumin solution) and crystalloid solutions (saline solution) in a 1:3 ratio or only crystalloid solutions.&#x0D; RESULTS AND DISCUSSION. A comparative evaluation of aging biomarkers before the procedure and 17 and 30 days after hardware plasmapheresis showed that therapeutic plasmapheresis affects the levels of human aging biomarkers in blood. A significant decrease in the levels of such biomarkers as homocysteine, urea, gamma-glutamyl transpeptidase, alkaline phosphatase, creatine phosphokinase, cholinesterase, and uric acid was shown. No significant differences were detected when we performed a comparative assessment of biochemical blood parameters following plasmapheresis with or without albumin replacement on biochemical blood parameters. Stable hemodynamic parameters during plasmapheresis and the absence of adverse reactions in patients confirm the safety and tolerability of the therapeutic plasmapheresis procedure.&#x0D; CONCLUSION. Implementing this technique into clinical practice will allow the development of approaches to etiotropic therapy of many chronic age-related pathologies. These treatments have the potential to increase life expectancy and improve its quality.

Senescent Cells: Dual Implications on the Retinal Vascular System.

Cellular senescence, a state of permanent cell cycle arrest in response to endogenous and exogenous stimuli, triggers a series of gradual alterations in structure, metabolism, and function, as well as inflammatory gene expression that nurtures a low-grade proinflammatory milieu in human tissue. A growing body of evidence indicates an accumulation of senescent neurons and blood vessels in response to stress and aging in the retina. Prolonged accumulation of senescent cells and long-term activation of stress signaling responses may lead to multiple chronic diseases, tissue dysfunction, and age-related pathologies by exposing neighboring cells to the heightened pathological senescence-associated secretory phenotype (SASP). However, the ultimate impacts of cellular senescence on the retinal vasculopathies and retinal vascular development remain ill-defined. In this review, we first summarize the molecular players and fundamental mechanisms driving cellular senescence, as well as the beneficial implications of senescent cells in driving vital physiological processes such as embryogenesis, wound healing, and tissue regeneration. Then, the dual implications of senescent cells on the growth, hemostasis, and remodeling of retinal blood vessels are described to document how senescent cells contribute to both retinal vascular development and the severity of proliferative retinopathies. Finally, we discuss the two main senotherapeutic strategies-senolytics and senomorphics-that are being considered to safely interfere with the detrimental effects of cellular senescence.

Prevalence and Risk Factors of Fundus Pathology in Patients with Type 2 Diabetes in a Northeastern Chinese Cohort

ABSTRACT Purpose To assess the prevalence of and risk factors for fundus pathology in patients with type 2 diabetes mellitus (T2DM) in a cohort from northeastern China. Methods Patients were included from the Fushun Diabetic Retinopathy Cohort Study. Patients aged ≥ 30 years with T2DM were recruited between July 2012 and May 2013. Fundus pathology included retinal vascular occlusion (RVO), age-related macular degeneration (AMD), macular pathology, pathologic myopia (PM) and glaucomatous optic atrophy (GOA). Results A Total of 1998 patients with gradable fundus photographs were included in this study, of whom 388 (19.42%) had fundus pathology regardless of whether they had diabetic retinopathy (DR). There were 187 (9.36%) patients with AMD, 97 (4.85%) with GOA, 67 (3.35%) with macular pathology, 35 (1.75%) with PM and 23 (1.15%) with RVO. Advanced age was significantly associated with AMD (odds ratio (OR), 95% confidence interval (CI): 1.03, 1.01–1.05), macular pathology (OR, 95% CI: 1.06, 1.03–1.09) and GOA (OR, 95% CI: 1.06, 1.04–1.09). A wider central retinal arteriolar equivalent was protective against PM (OR, 95% CI: 0.78, 0.66–0.92). Wider central retinal venular equivalent was a protective factor for PM (OR, 95% CI: 0.75, 0.68–0.82) and GOA (OR, 95% CI: 0.93, 0.87–0.99). Conclusions One-fifth of these patients in northeast China with T2DM had fundus pathology regardless of whether they had DR, indicating the importance of early screening and long-term follow-up.

Ginsenoside F1-Mediated Telomere Preservation Delays Cellular Senescence.

Telomeres play pivotal roles in processes closely related to somatic senescence and aging, making them a compelling target for interventions aimed at combating aging and age-related pathologies. Ginsenoside, a natural compound, has emerged as a potential remedy for promoting healthy aging, yet how it protects telomeres remains incompletely understood. Here, we show that treatment of F1 can effectively restore the level of TRF2, thereby preserving telomere integrity. This restoration leads to inhibition of the DNA damage response and improvements in mitochondrial function and, ultimately, delays in cellular senescence. Conversely, depletion of TRF2 causes mitochondrial dysfunction, accompanied by increased oxidative stress, autophagy inhibition, insufficient energy metabolism, and the onset of cellular senescence. These observations underscore the critical role of TRF2 in maintaining telomere integrity and direct association with the initiation of cellular senescence. We conduct a further analysis, suggesting F1 could bind in proximity to the TRF2 heterodimer interface, potentially enhancing dimerization stability. These findings suggest that F1 may be a promising natural remedy for anti-aging, and restoring TRF2 could potentially prevent telomere-dependent diseases commonly associated with the aging process.

Post-translational modifications and their implications in cancer.

Post-translational modifications (PTMs) are crucial regulatory mechanisms that alter the properties of a protein by covalently attaching a modified chemical group to some of its amino acid residues. PTMs modulate essential physiological processes such as signal transduction, metabolism, protein localization, and turnover and have clinical relevance in cancer and age-related pathologies. Majority of proteins undergo post-translational modifications, irrespective of their occurrence in or after protein biosynthesis. Post-translational modifications link to amino acid termini or side chains, causing the protein backbone to get cleaved, spliced, or cyclized, to name a few. These chemical modifications expand the diversity of the proteome and regulate protein activity, structure, locations, functions, and protein-protein interactions (PPIs). This ability to modify the physical and chemical properties and functions of proteins render PTMs vital. To date, over 200 different protein modifications have been reported, owing to advanced detection technologies. Some of these modifications include phosphorylation, glycosylation, methylation, acetylation, and ubiquitination. Here, we discuss about the existing as well as some novel post-translational protein modifications, with their implications in aberrant states, which will help us better understand the modified sites in different proteins and the effect of PTMs on protein functions in core biological processes and progression in cancer.

New Possibilities for Evaluating the Development of Age-Related Pathologies Using the Dynamical Network Biomarkers Theory.

Aging is the slowest process in a living organism. During this process, mortality rate increases exponentially due to the accumulation of damage at the cellular level. Cellular senescence is a well-established hallmark of aging, as well as a promising target for preventing aging and age-related diseases. However, mapping the senescent cells in tissues is extremely challenging, as their low abundance, lack of specific markers, and variability arise from heterogeneity. Hence, methodologies for identifying or predicting the development of senescent cells are necessary for achieving healthy aging. A new wave of bioinformatic methodologies based on mathematics/physics theories have been proposed to be applied to aging biology, which is altering the way we approach our understand of aging. Here, we discuss the dynamical network biomarkers (DNB) theory, which allows for the prediction of state transition in complex systems such as living organisms, as well as usage of Raman spectroscopy that offers a non-invasive and label-free imaging, and provide a perspective on potential applications for the study of aging.

Transcriptional changes of the aging lung.

Aging is a natural process associated with declined organ function and higher susceptibility to developing chronic diseases. A systemic single-cell type-based study provides a unique opportunity to understand the mechanisms behind age-related pathologies. Here, we use single-cell gene expression analysis comparing healthy young and aged human lungs from nonsmoker donors to investigate age-related transcriptional changes. Our data suggest that aging has a heterogenous effect on lung cells, as some populations are more transcriptionally dynamic while others remain stable in aged individuals. We found that monocytes and alveolar macrophages were the most transcriptionally affected populations. These changes were related to inflammation and regulation of the immune response. Additionally, we calculated the LungAge score, which reveals the diversity of lung cell types during aging. Changes in DNA damage repair, fatty acid metabolism, and inflammation are essential for age prediction. Finally, we quantified the senescence score in aged lungs and found that the more biased cells toward senescence are immune and progenitor cells. Our study provides a comprehensive and systemic analysis of the molecular signatures of lung aging. Our LungAge signature can be used to predict molecular signatures of physiological aging and to detect common signatures of age-related lung diseases.

Disrupted HSF1 regulation in normal and exceptional brain aging.

Brain aging is a major risk factor for cognitive diseases such as Alzheimer's disease (AD) and vascular dementia. The rate of aging and age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs and depend upon regenerative capacity and ability to manage damaged proteins and proteotoxicity. To answer these questions, we assessed age-dependent changes in brain stress responses with normally aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, and its regulation. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi-factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.

SIRT7: the seventh key to unlocking the mystery of aging.

Aging is a chronic yet natural physiological decline of the body. Throughout life, humans are continuously exposed to a variety of exogenous and endogenous stresses, which engender various counteractive responses at the cellular, tissue, organ, as well as organismal levels. The compromised cellular and tissue functions that occur because of genetic factors or prolonged stress (or even the stress response) may accelerate aging. Over the last two decades, the sirtuin (SIRT) family of lysine deacylases has emerged as a key regulator of longevity in a variety of organisms. SIRT7, the most recently identified member of the SIRTs, maintains physiological homeostasis and provides protection against aging by functioning as a watchdog of genomic integrity, a dynamic sensor and modulator of stresses. SIRT7 decline disrupts metabolic homeostasis, accelerates aging, and increases the risk of age-related pathologies including cardiovascular and neurodegenerative diseases, pulmonary and renal disorders, inflammatory diseases, and cancer, etc. Here, we present SIRT7 as the seventh key to unlock the mystery of aging, and its specific manipulation holds great potential to ensure healthiness and longevity.

Analysis of Behavior and Brain Neuronal Density in B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J Mice Modeling Parkinson’s Disease

Parkinson’s disease (PD) is a progressive age-related neurodegenerative pathology of the central nervous system, characterized by a selective loss of dopaminergic neurons of the nigrostriatal pathway and by the presence of specific inclusions (Lewy bodies) in dopamine neurons. To study the mechanisms of this pathology and to search for possible ways to correct it, genetic models of PD in mice have been created. Transgenic mice of the B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J strain (referred as B6.Cg-Tg further in the text) represent a model of PD, have the A53T mutation in the human alpha-synuclein gene. The aim of this work was to study the locomotor activity and the level of anxiety, as well as the density of neurons in the brain of male B6.Cg-Tg mice at the age of six months. Wild type C57BL/6J mice of the same sex and age were used as controls. The results of the current study demonstrate that B6.Cg-Tg mice are characterized by the high locomotor activity and the low anxiety. Besides, a selective decrease in the density of neurons in the subventricular zone, the substantia nigra, as well as the CA1, CA3, CA4 zones and the granular layer of the dentate gyrus of the hippocampus was observed in these mice. Thus, mice of the B6.Cg-Tg strain at the age of six months only partially correspond to the main pathophysiological signs of PD. Decrease in the density of neurons in the substantia nigra, as well as in the CA1 and CA3 zones of the hippocampus of B6.Cg-Tg mice resemble similar changes in PD. However, these mice demonstrated neither bradykinesia nor high level of anxiety.

The neurobiology and therapeutic potential of multi-targeting β-secretase, glycogen synthase kinase 3β and acetylcholinesterase in Alzheimer's disease.

Alzheimer's Disease (AD) is the most common form of dementia, affecting almost 50 million of people around the world, characterized by a complex and age-related progressive pathology with projections to duplicate its incidence by the end of 2050. AD pathology has two major hallmarks, the amyloid beta (Aβ) peptides accumulation and tau hyperphosphorylation, alongside with several sub pathologies including neuroinflammation, oxidative stress, loss of neurogenesis and synaptic dysfunction. In recent years, extensive research pointed out several therapeutic targets which have shown promising effects on modifying the course of the disease in preclinical models of AD but with substantial failure when transposed to clinic trials, suggesting that modulating just an isolated feature of the pathology might not be sufficient to improve brain function and enhance cognition. In line with this, there is a growing consensus that an ideal disease modifying drug should address more than one feature of the pathology. Considering these evidence, β-secretase (BACE1), Glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE) has emerged as interesting therapeutic targets. BACE1 is the rate-limiting step in the Aβ production, GSK-3β is considered the main kinase responsible for Tau hyperphosphorylation, and AChE play an important role in modulating memory formation and learning. However, the effects underlying the modulation of these enzymes are not limited by its primarily functions, showing interesting effects in a wide range of impaired events secondary to AD pathology. In this sense, this review will summarize the involvement of BACE1, GSK-3β and AChE on synaptic function, neuroplasticity, neuroinflammation and oxidative stress. Additionally, we will present and discuss new perspectives on the modulation of these pathways on AD pathology and future directions on the development of drugs that concomitantly target these enzymes.

Polyamines as Universal Bioregulators across Kingdoms and Their role in Cellular Longevity and Death

Polyamines (PAs) are important molecules that determine cell longevity or death. Studies have shown that nutritional supplementation with spermidine can reduce age-related pathology and increase life span in a number of organisms, including humans. In addition, applying PAs to plants prevents their senescence. This review aims to provide an integrated understanding of the regulation of PA metabolism and its effect(s) on cell homeostasis. PA metabolism is universal for plants and animals. Research has shown that increased levels of PA synthesizing enzymes are associated with cell proliferation, whereas activation of the PA catabolic pathway increases oxidative stress and leads to aging/senescence due to cellular damage. Intracellular PA levels are regulated at the transcriptional and translational levels of the PA metabolic genes. The cis-acting regulatory elements and transcription factors determine the tissue-, developmental stage-, and stress-specific expression of a gene. At the translational level, it is regulated by miRNAs targeting mRNAs for cleavage or translational suppression. The byproducts of PA metabolism, such as hypusine and acrolein, are important for cell survival or death. PAs and their metabolic enzymes play several other important roles in plant and animal physiology via their effects on chromatin condensation, histone acetylation, histone deacetylation, transmethylation, and protein-protein interactions. This review focuses on the role(s) of PAs as universal bioregulators in processes across kingdoms, with specific reference to regulation of cellular longevity and death.

Loss of stearoyl-CoA desaturase 2 disrupts inflammatory response in macrophages.

Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed "inflammaging." Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of Scd2 from macrophages dysregulated basal and bacterial lipopolysaccharide (LPS)-stimulated transcription of numerous inflammation-associated genes. Specifically, deletion of Scd2 from macrophages decreased basal and LPS-induced expression of Il1b transcript that corresponded to decreased production of precursor IL1B protein and release of mature IL1B. Furthermore, we identified disruptions in autophagy and depletion of unsaturated cardiolipins in SCD2-deficient macrophages. To assess the functional relevance of SCD2 in the macrophage response to infection, we challenged SCD2-deficient macrophages with uropathogenic Escherichia coli and found that there was impaired clearance of intracellular bacteria. This increased burden of intracellular bacteria was accompanied by increased release of pro-inflammatory cytokines IL6 and TNF but decreased IL1B. Taken together, these results indicate that macrophage expression of Scd2 is necessary for maintaining the macrophage response to inflammatory stimuli. This link between fatty acid metabolism and fundamental macrophage effector functions may potentially be relevant to diverse age-related pathologies. IMPORTANCE Macrophages are immune cells that respond to infection, but their dysfunction is implicated in many age-related diseases. Recent evidence showed that macrophage expression of a fatty acid enzyme, stearoyl-CoA desaturase 2, declines in aged organisms. In this work, we characterize the effects when stearoyl-CoA desaturase 2 is deficient in macrophages. We identify aspects of the macrophage inflammatory response to infection that may be affected when expression of a key fatty acid enzyme is decreased, and these findings may provide cellular insight into how macrophages contribute to age-related diseases.