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The Role of Lipids in Aging: Insights From C. Elegans

By Kathryn Atkins February 23, 2023 February 24, 2023 Blog

In a new study, researchers used C. elegans to investigate how changes in lipids during aging might impact lifespan and healthspan.

The Role of Lipids in Aging: Insights From C. Elegans

The Trending With Impact series highlights Aging publications (listed as “Aging (Albany NY)” by Medline/PubMed and “Aging-US” by Web of Science) that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Lipids are a diverse group of biomolecules that are essential for life, including fats, oils, waxes, and steroids, and play crucial roles in cell membrane structure, energy storage and signaling. Lipidomics is the comprehensive analysis of lipids and their interactions in biological systems, with an aim to understand the role of lipids in cellular processes and their association with diseases. As we age, our cells undergo complex changes, including alterations in cellular lipid profiles. These changes are not only confined to humans; organisms such as the nematode Caenorhabditis elegans (C. elegans) are also subject to changes in lipid composition during aging.

“For example, lipid classes including fatty acids (FA), triacylglycerols (TAG), sphingolipids (SL), and phospholipids (PL) have been identified as targets in lipid signatures related to aging [2, 3]. Furthermore, specific signatures are detected in the lipid profiles of those with age-related diseases, such as Alzheimer’s Disease [4–9]. In addition, the abundance of many fatty acid subtypes differs between the youth, elderly, and centenarians [10, 11].”

In a recent study, researchers Trisha A. Staab, Grace McIntyre, Lu Wang, Joycelyn Radeny, Lisa Bettcher, Melissa Guillen, Margaret P. Peck, Azia P. Kalil, Samantha P. Bromley, Daniel Raftery, and Jason P. Chan from Marian University, the University of Washington and Juniata College investigate the lipid profiles of C. elegans with mutations in the genes asm-3/acid sphingomyelinase and hyl-2/ceramide synthase during aging. On February 13, 2023, their research paper was published in Aging’s Volume 15, Issue 3, entitled, “The lipidomes of C. elegans with mutations in asm-3/acid sphingomyelinase and hyl-2/ceramide synthase show distinct lipid profiles during aging.”

The Study

In this study, the researchers focused on two enzymes that are important in the production of ceramides—a type of lipid that is known to play a role in various cellular processes, including cell signaling and apoptosis. The enzymes, acid sphingomyelinase 3 (asm-3) and ceramide synthase (Hyl-2), are involved in the breakdown of sphingomyelin and the synthesis of ceramide, respectively. The team compared C. elegans with mutations in these specific genes with wild type C. elegans at one-, five- and 10-days of age to investigate how changes in these enzymes affect lipid profiles during aging.

“In particular, work using C. elegans have identified age related changes in specific lipids, lipid classes, as well as the ratio of monosaturated to polysaturated fatty acids (MUFA:PUFA ratio) [36, 37]. Here, we examine the lipidomes of animals lacking the sphingolipid metabolism enzymes, asm-3/acid sphingomyelinase or hyl-2/ceramide synthase, which have previously been shown to have extended and reduced lifespans, respectively, in C. elegans [24, 34, 38].”

The results showed that the asm-3 mutant worms had higher levels of sphingomyelin and lower levels of ceramides compared to wild-type worms. In contrast, the hyl-2 mutant worms had lower levels of sphingomyelin and higher levels of ceramides. These findings suggest that asm-3 and Hyl-2 have opposite effects on the production of ceramides in C. elegans. The researchers also found that the lipid profiles of the mutant worms changed with age, with a decrease in sphingomyelin and an increase in ceramides in the asm-3 mutant worms and, in the hyl-2 mutant worms, there was an increase in sphingomyelin and a decrease in ceramides with age.

The researchers also investigated the effects of these lipid profile changes on lifespan and healthspan. They found that the asm-3 mutant worms had a shorter lifespan and reduced healthspan compared to wild-type worms. In contrast, the hyl-2 mutant worms had an extended lifespan and improved healthspan. These findings suggest that changes in lipid profiles can have significant effects on lifespan and healthspan in C. elegans.

Conclusions

Overall, this study sheds light on the complex role of lipids in aging and highlights the importance of ceramides in cellular processes. The findings suggest that changes in the production of ceramides, mediated by asm-3 and Hyl-2, can have significant effects on lifespan and healthspan in C. elegans. Further research in this area could lead to the development of interventions that target ceramide production to promote healthy aging in humans.

There are several potential implications of this study for human health. First, the findings suggest that interventions aimed at modulating ceramide production could have significant effects on aging-related diseases. Ceramide has been implicated in various diseases, including cancer, Alzheimer’s disease and diabetes. Targeting ceramide production could be a promising strategy for the prevention and treatment of these diseases.

Second, the study highlights the importance of understanding the complex interplay between lipids and cellular processes in aging. Aging is a complex process that involves multiple cellular and molecular changes, and alterations in lipid metabolism are just one aspect of this process. A better understanding of the role of lipids in aging could lead to the development of new interventions that target multiple aspects of the aging process.

Finally, the study underscores the importance of using model organisms, such as C. elegans, to investigate the molecular mechanisms of aging. While C. elegans is a simple organism, it shares many fundamental biological processes with humans, and its short lifespan makes it an ideal model for aging research. The findings from this study could be applied to future research in humans, as well as other model organisms, and could lead to the development of novel interventions for aging-related diseases.

“Age caused increased sphingomyelin levels, particularly in short-lived animals. This may suggest that the regulation of sphingolipid metabolism may mediate changes in cell structure and function important for healthy aging. Future studies connecting lipidomic changes in sphingolipid metabolism mutants to mechanistic changes in cells of mutant models will be important next steps to better understanding the roles of sphingolipids in aging.”

Click here to read the full research paper published by Aging.

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Aging is an open-access, peer-reviewed journal that has published high-impact research papers in all fields of aging research since 2009. These papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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BMI Correlates With Accelerated Epigenetic Aging in Young Adults

By Kathryn Atkins February 9, 2023 February 10, 2023 Blog

In a recent study, researchers from the University of Alabama at Birmingham’s Department of Pediatrics examined the relationship between measures of obesity and DNA methylation in young adults.

BMI Correlates With Accelerated Epigenetic Aging in Young Adults

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While the study of genetics focuses on heredity and alterations in the genetic code itself, epigenetics refers to the changes in gene expression that occur as a result of environmental or lifestyle factors. Advances in epigenetic research have allowed measures of DNA methylation (DNAm) (epigenetic clocks) to illustrate clear links between obesity, accelerated epigenetic aging and a variety of negative health outcomes in older adults. Despite these advances, there is a lack of research about these correlations and sex-based variations among young adults. The ability to detect accelerated epigenetic aging in young adulthood could potentially be used to prevent the onset of chronic diseases and improve health outcomes later in life.

“Moreover, few studies have included replication across measures of obesity and epigenetic aging to examine the robustness or specificity of these effects. Finally, little is known about sex differences in the links between obesity and epigenetic aging, despite evidence of substantial sex dimorphism in both physiological and epigenetic aging [20].”

In a recent study, researchers Christy Anne Foster, Malcolm Barker-Kamps, Marlon Goering, Amit Patki, Hemant K. Tiwari, and Sylvie Mrug from the University of Alabama at Birmingham’s Department of Pediatrics examined the relationship between obesity and measures of DNAm in young adults. They also investigated whether there is a sex-dependant correlation between obesity and DNAm in young adults. On January 18, 2023, their research paper was published in Aging’s Volume 15, Issue 2, and entitled, “Epigenetic age acceleration correlates with BMI in young adults.”

Research and Results

Here, the researchers explored the relationship between measures of obesity and epigenetic age acceleration in young adults. The team included a cross-sectional community sample of 290 healthy young adults—with 60% being female, 80% African American, 18% White, and a total mean age of 27 years old. The researchers measured participant BMI and waist circumference, and also calculated their epigenetic age acceleration using four epigenetic age estimators (derived from salivary DNA): Hannum DNAm, Horvath DNAm, Phenoage DNAm, and GrimAge DNAm. In addition, they collected data on covariates, including age, sex, race, parental education, and income-to-needs ratio.

After covariates were adjusted for, the researchers found that DNAm PhenoAge was higher in participants who had higher body mass index (BMI) and waist circumference in both sexes, with a stronger effect on BMI in males compared to females. Horvath DNA methylation age was associated with participants who had larger waist circumferences, but not BMI. Higher Hannum DNAm age was associated with both higher BMI and waist circumference in men, but not in women. In this study, GrimAge was not associated with either BMI or waist circumference. As a whole, none of the associations with the DNAm indicators varied by race. The researchers found that scoring higher on one or more of the four DNAm indicators was associated with an older chronological age, lower socioeconomic status, being female and White, as well as saliva cell composition.

“Together, these results suggest that higher BMI and waist circumference are associated with higher epigenetic age in young adulthood. Because the analyses adjusted for chronological age, associations with higher epigenetic age indicate faster epigenetic aging [22]. Importantly, this study demonstrated associations between obesity and epigenetic aging using DNA from saliva, which involves a non-invasive sample collection compared to other tissues (e.g., blood) and thus can be more readily translated into clinical practice, highlighting the usefulness in young adults.”

Significance and Limitations

These findings are significant because they suggest that body weight plays a role in determining epigenetic age acceleration, which in turn can affect overall health and lifespan. Previous research has shown that epigenetic age acceleration is associated with increased risk for age-related diseases such as cardiovascular disease, type 2 diabetes and certain cancers. However, it is important to note that this study only shows a correlation between BMI and epigenetic age acceleration and does not provide evidence of causality. It is possible that other factors, such as diet, exercise and stress levels, could also contribute to the relationship between BMI and epigenetic age acceleration.

The authors were forthcoming about several study limitations in their research paper, including a relatively small sample size which limited statistical power and precluded rigorous analysis of individual CpG sites. The original sample was locally representative but experienced some differential attrition over time, which could limit generalizability to certain populations. Epigenetic clocks have been tested primarily in White populations and may be less relevant to African American individuals who comprised the majority of this sample. This study used salivary DNA, so replication using DNA extracted from other tissues will be important for future work. The cross-sectional design did not allow testing directional effects between BMI and epigenetic aging over time. None of the CpGs used in calculating methylation age were part of known causal effect on BMI as per Mendelian Randomization studies; further modeling with outcomes from other tissues impacted by obesity may provide more insight into methylation aging process.

Conclusions

In conclusion, this study sheds light on the relationship between BMI and epigenetic age acceleration in young adults. The results suggest that young adults with higher BMIs may be aging faster and at a higher risk for age-related diseases. These findings highlight the importance of maintaining a healthy weight and lifestyle, not only for weight management but also for overall health and lifespan.

In the context of the growing obesity epidemic and the increasing focus on personalized medicine and preventive health, this study provides valuable insights into the potential health impacts of body weight and the role of epigenetics in health and disease. Further research is needed to fully understand the mechanisms behind this relationship and to determine the best approaches for improving health and lifespan in young adults.

“In conclusion, this study extends prior research by demonstrating the association between obesity and salivary epigenetic aging in young adult males and females. These findings are of interest to those who are interested in epigenetic age acceleration as a potential biomarker. They also support future research examining obesity as a causal risk factor for epigenetic age acceleration. The findings underscore the importance of testing sex differences and including multiple epigenetic clocks in future research. Overall, the present results add to mounting evidence that obesity affects cellular aging across multiple tissues early in the lifespan.”

Click here to read the full research paper published by Aging.

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Gene Linked to Osteoporosis Risk in Postmenopausal Asian Women

By Kathryn Atkins January 26, 2023 January 27, 2023 Blog

In this recent study, researchers compared three IGF-1 polymorphisms in postmenopausal Asian women and investigated their potential link to osteoporosis.

Gene Linked to Osteoporosis Risk in Postmenopausal Asian Women

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Osteoporosis is characterized by the loss of bone density and an increased risk of fractures. This serious health condition is a major public health concern, particularly among older women. According to the National Osteoporosis Foundation, approximately 80% of the estimated 10 million Americans with osteoporosis are women. Additionally, roughly one in two women over the age of 50 will break a bone due to osteoporosis.

“Osteoporosis (OP) is prevalent in postmenopausal women. Several studies investigated the association between IGF-1 polymorphisms and OP among postmenopausal females with conflicting outcomes.”

While the main risk factor for osteoporosis is undeniably aging, the causes of osteoporosis are more complex—involving a combination of genetic and environmental factors. The insulin-like growth factor 1 (IGF-1) gene plays a critical role in bone growth and development, and previous studies have suggested that variations in this gene may be associated with osteoporosis. Some genetic variants have been found to be associated with decreased IGF-1 levels, which may contribute to the development of osteoporosis.

In a recent study, researchers Sui-Lung Su, Yung-Hsun Huang, Yu-Hsuan Chen, Pi-Shao Ko, Wen Su, Chih-Chien Wang, and Meng-Chang Lee from the Tri-Service General Hospital and National Defense Medical Center in Taipei, Taiwan, explored the relationship between IGF-1 polymorphisms rs35767, rs2288377 and rs5742612 and the development of osteoporosis in postmenopausal Asian women. Their new research paper was published in Aging’s Volume 15, Issue 1, entitled, “A case-control study coupling with meta-analysis elaborates decisive association between IGF-1 rs35767 and osteoporosis in Asian postmenopausal females.”

“Although two meta-analyses have been published, conclusion of the association between IGF-1 and OP is pending, probably due to limited studies on postmenopausal women [21, 22].”

The Study

To further investigate the association between IGF-1 variants, osteoporosis and postmenopausal women, the researchers conducted a case-control study involving a cohort of postmenopausal women in Taiwan. The study included a total of 95 women with osteoporosis and 222 age-matched controls without this condition. The researchers genotyped the participants for the three IGF-1 variants and analyzed the data to determine the association between these variants and osteoporosis.

The results of the study revealed an association between the rs35767 variant and osteoporosis in these postmenopausal Asian women. Women with the variant had an increased risk of osteoporosis compared to those without the variant. In addition to the case-control study, the researchers also conducted a meta-analysis to combine the results of previous studies on the topic. This meta-analysis included their current findings and three other studies (published in English), totaling 2,267 individuals. The meta-analysis confirmed the results of their case-control study and found a significant association between the rs35767 variant and risk of osteoporosis in postmenopausal Asian women.

“We reveal a conclusive risk association in rs35767 with OP in postmenopausal females judged by TSA with 2,267 Asians in a combination of 3 published studies and our case-control study. However, rs2288377 and rs5742612 show no association with OP but it needs more sample sizes to evaluate the relationship.”

Conclusion

In conclusion, this research paper provides strong evidence for a decisive association between the rs35767 variant in the IGF-1 gene and the development of osteoporosis in postmenopausal Asian women. The study suggests that this variant may be a significant genetic risk factor for osteoporosis in this population. Their research could help in understanding the genetic basis of osteoporosis and also pave the way for personalized medicine in the management of this condition in the future. Identifying individuals at high risk for osteoporosis based on their genetic profile could allow for early detection and interventions to prevent or delay the onset of this disease. However, more research is needed to confirm these findings in other populations and to compare this study with other studies that have not been documented in the English language.

“To conclude, our case-control study is a crucial sample in meta-analysis to reach [the] conclusion of the association between IGF-1 rs35767 and OP in postmenopausal women.”

Click here to read the full research paper published by Aging.

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New Insights Into the Mechanisms of Sarcopenia

By Kathryn Atkins December 9, 2022 December 9, 2022 Blog

In this new study, researchers aimed to further elucidate the mechanisms of sarcopenia by examining the influence of denervation in young and middle-aged mice.

New Insights Into the Mechanisms of Sarcopenia

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A hallmark characteristic of aging is the progressive loss of skeletal muscle mass, known as sarcopenia. A process called motor neuron denervation (Den)—when nerve signals to muscles are blocked or reduced—leads to muscle atrophy, fatigue and eventually muscle loss. Determining how and when Den events influence older muscles is crucially important for developing interventions to stop or reverse age-related muscle wasting.

“Further, aged muscle exhibits reduced plasticity to both enhanced and suppressed contractile activity. It remains unclear when the onset of this blunted response occurs, and how middle-aged muscle adapts to denervation.”

Dysfunctional mitochondria in muscle tissue are known to increase with age. Lysosomes are responsible for the recycling of damaged mitochondria. However, as muscles age, lysosomal function in muscle tissue also declines.

In a new study, researchers Matthew Triolo, Debasmita Bhattacharya and David A. Hood from York University in Toronto, Canada, aimed to characterize the time-dependent changes in denervated skeletal muscle from middle-aged mice. The team focussed on how mitochondrial turnover is impacted. On November 4, 2022, their research paper was published in Aging’s Volume 14, Issue 22, entitled, “Denervation induces mitochondrial decline and exacerbates lysosome dysfunction in middle-aged mice.”

The Study

“The purpose of this study was to compare mitochondrial turnover pathways in young (Y, ~5months) and middle-aged (MA, ~15months) mice, and determine the influence of Den.”

Male mt-Keima mice aged 4-6 months (young) and 14-16 months (middle-aged) were included in this study. The researchers performed surgical procedures to induce Den in the hindlimb muscles of the study mice. After one, three, or seven days of Den, tissue was excised and imaged using confocal microscopy. The researchers collected whole-muscle protein extracts and conducted Western blotting. Statistical analysis was performed using the data they collected.

The middle-aged muscles were compared to muscles from control and young mice. The researchers found that muscle mass, mitochondrial content and PGC-1α protein levels were not different between the young and middle-aged mice. However, indications of enhanced mitochondrial fission and mitophagy and a greater abundance of lysosome proteins were evident in the middle-aged muscle. Their data suggest that increases in fission drive an acceleration of mitophagy in middle-aged murine muscle in order to preserve mitochondrial quality.

“Den exacerbates the aging phenotype by reducing biogenesis in the absence of a change in mitophagy, perhaps limited by lysosomal capacity, leading to an accumulation of dysfunctional mitochondria with an age-related loss of neuromuscular innervation.”

Conclusion

“In our present study, the inability to upregulate mitophagy flux with denervation is driven by a combination of 1) failure to increase mitophagic proteins and 2) the appearance of dysfunctional lysosomes.”

This latest study may shed light on how muscles age and reveal the importance of mitophagy and lysosomal function in maintaining healthy muscles among middle-aged mice. The study also highlights that denervation induces mitochondrial decline and exacerbates lysosome dysfunction in muscles, thereby worsening age-related muscular atrophy. Further studies are needed to gain a deeper understanding of the mechanisms behind these changes and how they can be prevented or reversed.

“Thus, therapies to combat muscle wasting with age-related physiologic denervation must be designed accordingly. Our results imply targeting both mitochondrial biogenesis and maintenance of lysosome capacity will serve to restore mitochondrial homeostasis and likely metabolic capacity of skeletal muscle.”

Click here to read the full research paper published by Aging.

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Aging is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Is Estrogen Dysregulation Behind Alzheimer’s Pathology?

By Kathryn Atkins November 18, 2022 November 22, 2022 Blog

In a new study, researchers explored Alzheimer’s disease and its potential relationship with the estrogen receptor-α gene (ESR1).

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The United States government currently has a mind-blowing annual budget of $3.5 billion designated for Alzheimer’s disease (AD) and dementia research funding. Therapeutics pushed forward thus far have been largely based on the amyloid-beta (Aβ) cascade hypothesis of AD. Surprisingly, despite decades and billions, these interventions have yielded little to no benefits for AD patients. This lack of efficacy has encouraged some researchers to rethink AD pathology and focus on discovering key triggers and mechanisms of neuroinflammation.

“There has been a lengthy and ongoing scientific debate around the causative factors of AD, and the relative importance of both senile Aβ plaques and tau tangles has been largely informed by postmortem investigations of the AD brain. For several decades, the amyloid hypothesis has dominated the field, which has brought forth many high-profile therapeutic attempts that have produced side effects but no real benefits [5].”

Women & Alzheimer’s Disease

Women compose two-thirds of the United States Alzheimer’s population. Is this gender-specific risk a result of living longer or is it due to other causes, perhaps related to hormonal differences or gender-associated differential gene expression? Previous studies have found that estrogen may protect neurons from the damaging effects of amyloid-beta plaques and tau tangles. However, in women, estrogen levels tend to decline with age, which could be one reason why aging women are more susceptible to AD.

In a new study, researchers Junying Liu, Shouli Yuan, Xinhui Niu, Robbie Kelleher, and Helen Sheridan from Trinity College Dublin, Peking University and Jilin University examined the potential relationship between the estrogen receptor-α gene (ESR1) and neuroinflammation. Their research paper was published on November 1, 2022, in Aging’s Volume 14, Issue 21, and entitled, “ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer’s disease process.”

“AD is characterized by three major questions: Why is age the primary risk factor? Why are women more sensitive to the onset of this form of dementia? And why are neurons in areas of the brain that are essential for memory selectively targeted?”

The Study

Originally, the researchers in this study had been in the process of investigating ESR1-knockdown in breast cancer when they stumbled upon another discovery. (ESR1 is a gene that codes for the estrogen receptor, a protein that helps to regulate cell division and differentiation.) To their surprise, KEGG pathway enrichment analysis showed that ESR1 may also be related to axonal guidance, inflammation-related gene markers and Notch signaling pathways. Upon further validation using a dataset of in vivo AD inflammatory samples, the team found that the ESR1 gene was altered in AD patients and was associated with an increase in pro-inflammatory markers.

“ESR dysfunction likely plays a role in AD pathology – especially in women – although the specific mechanisms remain unclear. In vivo and ex vivo studies demonstrate that neuroinflammatory brain states overlap with ESR signaling pathways and that these two systems interact closely.”

In the current study, the researchers used an animal model to explore the potential role of ESR1 in modulating inflammation-related AD pathology. Using a macrophage cell line, they identified ESR1 as a key modulator of inflammation in the context of AD. They then showed that when the ESR1 gene was absent or mutated, neuroinflammation occurred. This finding offers a potential mechanism for understanding the gender-specific risk of AD in women.

“Our results suggest that ESR1 is modulated by apolipoprotein E (APOE) through CEBPB/ATF4, mir-155-5p, or mir-1-3p. Moreover, sea hare-hydrolysates (SHH), as one of the axonal guidance molecules, could regulate the STAT3/PRDM1/CEBPB pathway and consequently induce cell death through pyroptosis signaling pathways, trigger the secretion of IL1β, leading to neuroinflammation and worsening AD pathogenesis. Molecular docking verification demonstrated that the predicted natural products scoulerine and genistein displayed strong binding affinities for BACE1 and ESR1, respectively. This strategy can be used to design novel, personalized therapeutic approaches to treatment and a first-in-class clinical lead for the personalized treatment of AD.”

Conclusion

The research team concluded that further studies are needed to elucidate the exact mechanisms through which ESR1 modulates inflammation and its role in Alzheimer’s disease. These findings may offer a novel therapeutic direction for treating AD. Therapeutics targeting ESR1 could potentially be used to reduce inflammation in the brain and prevent AD progression. This may be beneficial for both men and women afflicted with this devastating disease.

“Unfortunately, despite enormous efforts, there remains no cure for this terrible illness, and current treatments merely alleviate its devastating symptoms for a short time. This study performed several bioinformatics-based analyses, concluding that ESR1 dysfunction might mediate axonal guidance, induce neuroinflammation or pyroptosis in the brain, and subsequently worsen AD conditions.”

Click here to read the full research paper published by Aging.

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Investigating Susceptibility to Radiation-Induced Pulmonary Fibrosis

By Kathryn Atkins October 20, 2022 October 20, 2022 Blog

Researchers evaluated three different mouse strains with varying sensitivity to radiation lung fibrosis in an effort to uncover the underlying mechanisms.

Investigating Susceptibility to Radiation-Induced Pulmonary Fibrosis

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Radiation is an effective treatment for many types of cancer. Unfortunately, this treatment has the potential to cause long-term side effects in some patients, including the thickening or scarring of lung tissue, known as pulmonary fibrosis. Radiation-induced pulmonary fibrosis (RIPF) is a serious complication that can occur after radiation therapy and can lead to death. Predicting an individual’s risk of developing RIPF remains challenging for clinicians, as little is known about the underlying mechanisms that cause it.

“Differential susceptibility to lung injury from radiation and other toxic insults across mouse strains is well described but poorly understood.”

Previous studies in mouse models have shown that there are natural variations in susceptibility to RIPF among different strains of mice. The mechanism(s) underlying this difference in susceptibility is still unknown. In a new study, researchers Eun Joo Chung, Seokjoo Kwon, Uma Shankavaram, Ayla O. White, Shaoli Das, and Deborah E. Citrin from the National Institutes of Health’s National Cancer Institute investigated differences in macrophage function across mouse strains and their potential contribution to varied RIPF susceptibility. On September 28, 2022, their research paper was published in Aging’s Volume 14, Issue 19, entitled, “Natural variation in macrophage polarization and function impact pneumocyte senescence and susceptibility to fibrosis.”

The Study

While the precise mechanisms underlying RIPF are not fully understood, it is thought that senescent pneumocytes (or alveolar cells) play a key role. Pneumocytes are a type of cell in the lung that are essential for gas exchange. Type II pneumocytes (AECII) function as alveolar stem cells after lung injury. The researchers hypothesized that macrophages (a type of white blood cell that play an important role in immune responses) may contribute to promoting AECII senescence.

“AECII are known to be in close contact with alveolar macrophages, and, in this fashion, to contribute to lung homeostasis [11].”

The researchers hypothesized that natural variations in macrophage function contribute to differences in RIPF susceptibility. To explore their hypothesis, they evaluated three different mouse strains with varying sensitivity to radiation lung fibrosis: C57L mice (RIPF-prone), C57BL6/J mice (intermediate) and C3H/HeN mice (RIPF-resistant). Female mice (to avoid sex-based differences in results) underwent thoracic irradiation (IR). Changes in macrophages and pneumocytes were assessed.

The Results

The team found that susceptibility to radiation-induced lung injury and premature AECII senescence varied by mouse strain. Pulmonary irradiation led to varied macrophage phenotypes and accumulation in each strain. In responses to polarizing stimuli, macrophages demonstrated strain-dependent responses. M2 macrophages induced AECII senescence via NOX2-derived superoxide production in a strain-dependent manner. Finally, macrophages expressing NOX2 accumulated in fibrotic lungs after radiation.

“NOX1 and NOX2 protein were expressed at the highest levels in C57L BMDM, with intermediate expression in C57BL6/J BMDM and the lowest expression in C3H/HeN BMDM (Figure 6B).”

The researchers demonstrated that the C57L mice (the strain with the greatest sensitivity to RIPF) exhibited the greatest rate of accumulation of senescent AECII cells. At the same time, they found that the fibrosis-sensitive (C57L and C57Bl6/J) mouse strains exhibit a greater accumulation of M2 polarized macrophages than the fibrosis-resistant strain (C3H/HeN).

“However, until now, the impact of M2 polarization on AECII senescence was unexplored. In this study, we identified that M2 macrophage polarization can contribute to AECII senescence, potentially leading to a positive feedback loop that furthers pulmonary injury.”

Conclusion

This study provides new insights into the role of macrophages in RIPF susceptibility. The findings suggest that natural variations in macrophage function contribute to differences in RIPF susceptibility. The different macrophage polarization profiles across strains may contribute to their varying susceptibilities to RIPF by promoting AECII senescence. These findings may help to develop new strategies for the prevention and treatment of RIPF.

“In this study, variation in the accumulation of senescent cells across strains with varying sensitivity to fibrosis has been established. Further, strain variation in macrophage response to polarizing stimuli and capacity to produce superoxide and induce senescence in epithelial cells is described. Together, these data highlight the importance of macrophage-epithelial interactions in the context of lung fibrosis and identify NOX2 as a possible therapeutic target in radiation lung injury.”

Click here to read the full research paper published by Aging.

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Does A Link Exist Between Longevity, Aging and Heart Rate Parameters?

By Kathryn Atkins October 13, 2022 October 14, 2022 Blog

Researchers investigated the relationship between familial longevity, chronological age and heart rate parameters, including heart rate variability and 24-h rhythms.

ecg ekg screen, heart rate — Closeup view of an ECG/EKG display

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A normal resting heart rate (HR) for adults should be anywhere between 60 and 100 beats per minute. A low resting heart rate has been associated with better overall health and fitness. Crosswise, a higher resting heart rate appears to have a strong correlation with mortality. Heart rate variability (HRV), the beat-to-beat changes in heart rate, is indicative of the heart’s ability to respond to changes in physical and emotional stress. Low HRV has been shown to be a risk factor for heart disease, while high HRV has been associated with good heart health. Although HR and HRV are frequently studied, these parameters are not often investigated continuously or over long periods of time in healthy, middle-aged individuals.

“Parameters of HR and HRV are often investigated during a short electrocardiogram (ECG) measurement at the study center or in the hospital, but not continuously over a longer period while individuals continue with their daily lives.”

The Study

In a new study, researchers Janneke M. Wiersema, Annelies E.P. Kamphuis, Jos H.T. Rohling, Laura Kervezee, Abimbola A. Akintola, Steffy W. Jansen, P. Eline Slagboom, Diana van Heemst, and Evie van der Spoel from Leiden University Medical Center and Catharina Hospital used continuous ambulatory ECG measurements collected over a period of 24 to 90 hours to investigate the relationship between heart rate parameters and familial longevity and chronological age. On August 16, 2022, their research paper was published in Aging’s Volume 14, Issue 18, and entitled, “The association between continuous ambulatory heart rate, heart rate variability, and 24-h rhythms of heart rate with familial longevity and aging.”

“This is one of the first studies to look at the relationship between parameters of HR, HRV, and 24-h rhythms in HR based on continuous ambulatory ECG measurements over a period of several days with both familial longevity and chronological age in a single design.”

The majority of the recruited study participants were middle-aged and from the Leiden Longevity Study (LLS): 37 offspring of long-lived families between 52 and 83 years old, and 36 of their partners/spouses of the same age range. In addition, the researchers recruited 35 younger individuals from the Switchbox Leiden Study between 18 and 40 years old. All study participants were asked to wear a small heart rate monitor, the Equivital EQ02 life monitor (EQ02), for 24 to 90 hours. They were then instructed to carry on with their daily lives and regular routines.

Results & Conclusion

After data cleaning and statistical analyses, no association between heart rate parameters and familial longevity was found. However, middle-aged participants had lower 24-hour heart rates (average and maximum HR, not minimum HR), lower amplitudes, and earlier trough and peak times than the young participants. During long-term EQ02 recordings, middle-aged participants showed a less optimal HRV in both the sleep and awake periods. The researchers believe this might indicate that older hearts are less adaptable than those in the young.

“This could be a first indication of deteriorated cardiovascular health in middle-aged individuals.”

The researchers were forthcoming about the limitations of this study. The study sample was relatively small, there was no standardization of daily activities among the participants, and any potential medications used by the younger participants were not adjusted for (as they were for the middle-aged participants). Despite these limitations, this study provides novel insight into heart rate parameters over longer periods of time and in relation to familial longevity and chronological age.

“In our study, we can conclude that resting HR during the sleep period is not associated with familial longevity or chronological age. This study showed that continuous ambulatory ECG measurements can be used to obtain adequate information on HR, HRV and 24-h rhythms in HR, which was also showed by others [50]. However, the small sample size, due to the poor quality of a part of the data, is a limitation of this study and should be improved in future studies. Furthermore, we suggest for future research to control for exercise and day planning between groups. Lastly we suggest to include an additional group with participants of an older age than the middle-aged group, and to investigate the relation between health status and HR parameters.”

Click here to read the full research paper published by Aging.

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Adenoviral COVID-19 Vaccine Elicits Robust Immunity in Elderly Cohort

By Kathryn Atkins October 5, 2022 October 6, 2022 Blog

In a trending new study, researchers investigated the efficacy of an adenoviral-based COVID-19 vaccine in elderly patients.

Adenoviral COVID-19 Vaccine Elicits Robust Immunity in Elderly Cohort

The Trending With Impact series highlights Aging publications (listed as “Aging (Albany NY)” by MEDLINE/PubMed and “Aging-US” by Web of Science) that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Around the world, more than 180 COVID-19 vaccines are currently in production or development. Some COVID-19 vaccines have been less effective in the elderly—a population that is already highly vulnerable to severe viral infection. Humoral immunity, or antibody-mediated immunity, is an important weapon against COVID-19. Immune responses in the elderly are often hindered by aging, an unfortunate process known as age-related immunosenescence. Vaccines that can successfully elicit a robust humoral immune response in the elderly are critical for achieving COVID-19 immunity and interrupting disease transmission in this population.

“The development of an effective vaccine against SARS-CoV-2 targeted for an elder population is a challenge [17]. Furthermore, there is limited data describing the behavior of COVID-19 vaccines when administered to the elderly.”

Sputnik V

The two most widely available vaccines in the United States are both mRNA vaccines, the Pfizer-BioNTech and Moderna vaccines. Of course, there are other vaccines that are more commonly available in other countries, such as Gam-COVID-Vac, or Sputnik V. Sputnik V is an adenoviral-based SARS-CoV-2 vaccine.

“Gam-COVID-Vac (Sputnik V), uses a heterologous recombinant adenovirus 26 (Ad26) and adenovirus 5 (Ad5) as vectors that deliver the genetic sequence of the SARS-CoV-2 Spike protein, has been administered to tens of millions of volunteers worldwide, and has a good tolerability profile [14, 15].”

Adenoviral-based vaccines use a weakened form of a common cold virus (adenovirus) to deliver the genetic instructions for making the SARS-CoV-2 spike protein. When these instructions are delivered to human cells, they cause the cells to produce the spike protein. The body then produces antibodies against the spike protein, which provides immunity against SARS-CoV-2. In early 2021, Sputnik V was the only vaccine available to the elderly in Argentina. The ability of this particular vaccine to elicit humoral immunity in this elderly population had yet to be fully investigated.

The Study

In a new study, researchers Rodrigo Hernán Tomas-Grau, Carolina Maldonado-Galdeano, Mónica Aguilar López, Esteban Vera Pingitore, Patricia Aznar, María Elena Alcorta, Eva María del Mar Vélez, Agustín Stagnetto, Silvana Estefanía Soliz-Santander, César Luís Ávila, Sergio Benjamín Socias, Dardo Costas, Rossana Elena Chahla, Gabriela Perdigón, Rosana Nieves Chehín, Diego Ploper, and Silvia Inés Cazorla from Instituto de Investigación en Medicina Molecular y Celular Aplicada, Centro de Referencia para Lactobacilos, Public Healthcare Administration (SIPROSA), and Néstor Kirchner Hospital investigated whether Gam-COVID-Vac could induce a robust humoral immunoresponse in elderly patients. On September 21, 2022, their research paper was published in Aging’s Volume 14, Issue 18, entitled, “Humoral immunoresponse elicited against an adenoviral-based SARS-CoV-2 coronavirus vaccine in elderly patients.”

In this study, 149 volunteers between 70 and 96 years old received two doses of the Sputnik V vaccine between December 2020 and February 2021. The researchers took blood samples from the participants before vaccination and 14, 28, 90, and 180 days post-vaccination (dpv). The researchers used the blood samples to analyze the humoral immune responses (antibodies) that were elicited by Sputnik V.

Results & Conclusion

The results showed that Sputnik V elicited robust anti-RBD immune responses in the elderly volunteers. The researchers found that the younger participants and the participants with previous COVID-19 infection had higher anti-RBD immune responses. They also found that humoral immune responses did not vary by gender at early time points. However, concentrations of antibodies were more persistent in elderly females than males at 60 dpv, and only dropped at 90 dpv.

“Our results show that Gam-COVID-Vac was able to deal with the ageing of the immune system, eliciting a robust immune response in an elderly cohort, which lasted approximately 90 dpv at high levels, and protected against COVID-19.”

Immunization with Sputnik V may be a promising vaccine for the prevention of severe COVID-19 disease in elderly patients. This suggests that adenoviral-based vaccines could be a safe and effective option for protecting elderly patients against COVID-19 and other emerging infectious diseases. However, additional studies are needed to further evaluate the safety profile and efficacy of this vaccine in elderly patients. If this vaccine proves to be effective in preventing COVID-19 in the elderly, it could have a profound impact on public health.

“As the aging population is increasing globally, especially in developed countries, vaccine efforts must consider age-related issues in order to ensure effectiveness. Ongoing studies will provide data regarding the best strategy to strengthen and prolong the protective immune response against COVID-19 in the elder population, challenging the immunosenescence process, to ameliorate the severity of the disease and avoid the SARS-CoV-2 infection.”

Click here to read the full research paper published by Aging.

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Unborn Children Exposed to Common Chemical Leads to Fertility Defects

By Kathryn Atkins September 29, 2022 September 30, 2022 Blog

In a trending new study, researchers investigated a common chemical and its multigenerational effects on fertility and ovarian function.

Unborn Children Exposed to Common Chemical Leads to Fertility Defects

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The food, beverages and products that women are exposed to before and during pregnancy can have lifelong consequences for babies in the womb. This concept is known as fetal programming. Introducing endocrine-disrupting chemicals (EDCs; toxins) during critical moments of fetal development can significantly impact the child’s health, development and fertility. These negative impacts may even compound in future generations.

“However, our understanding of the negative effects of chemicals on health in women is less than those in men [24].”

Acrylamide

Frying, roasting or baking starchy food at high temperatures produces a Maillard reaction. A problematic result of this reaction is the formation of a chemical compound called acrylamide (ACR). Acrylamide can be found in many common foods, including french fries, chips, bread, crackers, coffee, and so on. Exposure to this chemical during pregnancy has been linked to reduced development and reproductive function.

“Based on the formation of ACR in food during high temperatures and its presence in water and cosmetics [25, 26], this potential EDC may constitute a major problem for human health and could notably affect female fertility by influencing the ovary structure and function.”

While the effects of ACR in-utero have been documented, researchers Nouf Aldawood, Maroua Jalouli, Abdulkarem Alrezaki, Saber Nahdi, Abdullah Alamri, Mohamed Alanazi, Salim Manoharadas, Saleh Alwasel, and Abdel Halim Harrath from King Saud University wondered how exposure to acrylamide impacts health, development and fertility after a second generation. In a new study, the team investigated exposure to this toxin and its effects on ovarian function over the course of two generations of rats. On September 6, 2022, their research paper was published in Aging’s Volume 14, Issue 17, and entitled, “Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging.”

The Study

“In our current study, the focus was on the effect of ACR during pregnancy on the ovarian function extended over two successive generations as the ovaries are considered one of the most sensitive organs to toxic substances and exposure during the fetal stage.”

The researchers raised 20 healthy female Wistar-Albino rats and mated them. Between gestation days six and 21 (delivery), five pregnant rats were dosed daily with distilled water (the control group; no ACR), five pregnant study rats were dosed daily with 2.5 mg/kg of ACR, five pregnant study rats were dosed with 10 mg/kg of ACR, and the last five pregnant rats were dosed with 20 mg/kg of ACR. Offspring exposed to ACR, or animals of the first generation (AF1), were collected, as were the offspring of the control group (CF1). Blood samples were collected and ovaries were assessed at four weeks of age. AF1 and CF1 rats were raised until maturity and mated again. All pregnant rats were dosed depending on what/how much their mother received. The AF1 and CF1 rats gave birth to the second generation: the AF2 and CF2 offspring. Again, blood samples were collected and ovaries were assessed at four weeks of age.

Results

The researchers found that the first generation of offspring from the rats dosed with ACR (AF1) had ovaries that weighed significantly more than those in the control group (CF1). Upon histoarchitecture examination of the ovaries, this weight increase may have been caused by ovarian cysts that were identified within the AF1 rats and indicated a disruption in ovarian function. Interestingly, the results were quite different in AF2 rats. The researchers were surprised to find that prenatal ACR exposure in the second generation decreased ovarian weights and increased estradiol levels, CYP19 mRNA levels and CYP19 protein expression in all three study groups. These findings in the AF2 rats indicated early ovarian aging.

“In this study, we found that the first generation reacted differently from the second generation. Indeed, maternal exposure to ACR caused an ovarian disruption in AF1 as evidenced by severe histopathological damage, development of cysts, and high apoptosis in the stroma cells, and decreased plasmatic estradiol levels and its corresponding CYP19 gene and protein expression. However, it has induced early ovarian aging in AF2 characterized by high estradiol and progesterone levels, upregulation of CYP19, and apoptotic cell death in the stroma.”

Conclusion

“Altogether, the present study suggests that the in utero multigenerational exposure to ACR highly reduced fertility and ovarian function in females of the first generation, while it has induced early ovarian aging in females of the second generation.”

This may be the world’s first study to examine the multigenerational impact of ACR exposure on ovarian function and fertility in female rat offspring. This study provides evidence that in-utero exposure to ACR can lead to ovarian dysfunction and accelerated ovarian aging. Ovarian aging is not only a potential barrier to fertility but also a major risk factor for ovarian cancer. Women should take fetal programming into grave consideration when pregnant. Results from this study have important implications for human health and fertility.

“Moreover, this study provides some interesting evidence for the eventual implication of the epigenetic impacts of endocrine disruptors on female reproduction across generations. Future studies, using genome wide DNA methylation approaches for some specific key biomarkers of ovarian development, such as CYP19, are fundamental to determine how prenatal exposure to endocrine disruptors could drive adverse secondary phenotypic effects among the future generations in both humans and animals.”

Click here to read the full research paper published by Aging.

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Stroke Outcomes Mediated by These 2 Mechanisms

By Kathryn Atkins August 25, 2022 August 26, 2022 Blog

In a trending new research paper published in Aging, researchers investigated the effects of microglial activity on post-stroke inflammation and outcomes.

Stroke Outcomes Mediated by These 2 Mechanisms

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When the blood supply in and around the brain becomes interrupted, a stroke can occur. A hemorrhagic stroke is when a blood vessel bursts in or near the brain. An ischemic stroke is caused when a blood vessel carrying oxygen and nutrients to the brain is obstructed—usually by a clot. The most common type of stroke is ischemic, which accounts for approximately 87% of all strokes in humans. A major risk factor for an ischemic stroke is aging.

Inflammation (a chronic condition among the elderly) is a key contributing factor to strokes, and microglia are the primary immune cells in the brain. Researchers recently identified a role for the microglial IRF5-IRF4 regulatory axis in mediating responses after stroke. However, whether or not aged microglia also undergo the same regulatory mechanisms after a stroke had previously not been determined.

“Microglial activation plays a central role in initiating and perpetuating the post-stroke inflammation, and acts as a ‘double-edged’ sword to confer both detrimental and beneficial effects [9].”

In a recent study, researchers Conelius Ngwa, Abdullah Al Mamun, Shaohua Qi, Romana Sharmeen, Yan Xu, and Fudong Liu from The University of Texas Health Science Center at Houston investigated aged mice and the role of the microglial IRF5-IRF4 regulatory axis after a stroke. On August 12, 2022, their research paper was published in Aging’s Volume 14, Issue 15, and entitled, “Regulation of microglial activation in stroke in aged mice: a translational study.“

The Study

“We have previously found IRF4 signaling is anti-inflammatory and IRF5 is pro-inflammatory in young ischemic microglia [11]. In the present study, we hypothesized IRF4 CKO [conditional knockout] worsens while IRF5 CKO improves stroke outcomes.”

To better understand how microglia responds to stroke in aged individuals, the researchers first investigated microglial IRF5 and IRF4 expression in young and aged mice. A well-established mouse model of ischemic stroke was used in this study. Next, the researchers performed conditional knockout (CKO) of IRF5 or IRF4 in young and aged mice. The study arm mice underwent a 60-minute middle cerebral artery occlusion (MCAO). Stroke outcomes were quantified three days after MCAO.

To evaluate microglial activation and immune responses (surface and intracellular inflammatory markers) post-stroke, the researchers performed flow cytometry and enzyme-linked immunosorbent assay (ELISA). IRF5 CKO aged microglia had significantly lower levels of IL-1β and CD68 compared to controls. IRF4 CKO had significantly higher levels of IL-1β and TNF-α compared to control microglia. Levels of anti-inflammatory cytokines IL-4 and IL-10 were higher in IRF5 CKO, and lower in IRF4 CKO aged mice.

“Plasma levels of TNF-α and MIP-1α were decreased in IRF5 CKO vs. flox aged mice, and IL-1β/IL-6 levels were increased in IRF4 CKO vs. controls.”

Results & Conclusion

Since IRF5 signaling drives microglial pro-inflammatory responses, the researchers hypothesized that microglial IRF5 is detrimental for aged mice in stroke. They also suggested that IRF4 signaling drives anti-inflammatory responses and its expression is protective in aged mice in stroke. Indeed, IRF5 CKO aged mice demonstrated improved stroke outcomes; whereas worse outcomes were seen in IRF4 CKO mice compared to their control counterparts. Furthermore, the results of this study demonstrated that aged microglia express higher levels of IRF5 and lower levels of IRF4 compared to young microglia after stroke.

This study provides valuable insights into how microglial activation is regulated post-stroke, and highlights the importance of the IRF5-IRF4 axis in stroke outcomes. The researchers conclude that the IRF5-IRF4 axis is a promising target for developing novel strategies to treat ischemic stroke. Further research is warranted to determine how these findings can be translated into clinical practice to improve stroke outcomes in the elderly.

“By using the aged IRF4/IRF5 microglial CKO mouse models, the study aimed to selectively suppress microglial pro-inflammatory activation and promote its anti-inflammatory response, and will potentially help develop new, effective therapeutic strategies against stroke.”

Click here to read the full research paper published by Aging.

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