Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in
            <i>Drosophila</i>

Rera, Michaël; Clark, Rebecca I.; Walker, David W.

doi:10.1073/pnas.1215849110

Cited by 520 publications

(814 citation statements)

References 41 publications

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“…Maintaining insulin sensitivity by eliminating chronic low-grade inflammation (which may be the result of MT) could support muscle repair and regeneration, thus aiding the maintenance of muscle mass and function in aging. Invertebrate studies support this direct link between intestinal barrier function and physical function, muscle mass, and myocyte apoptosis (Rera et al, 2012;Ulgherait et al, 2014). Means with standard errors of the mean presented in parentheses are shown Stehle et al reported that greater MT was associated with worsening physical function in older people and that this relationship was also independent of inflammatory cytokines (Stehle et al, 2012), consistent with results from the current study.…”

Section: Discussionsupporting

confidence: 89%

“…Intestinal Bleakiness^occurs with advancing age across many species (Ma et al, 1992;Rera et al, 2012;Tran and Greenwood-Van Meerveld, 2013;Ghosh et al, 2014), but only recently has become recognized as an important mediator of healthspan, lifespan, and insulin signaling in invertebrates (Rera et al, 2012;Ulgherait et al, 2014). A Bleaky^mucosa allows greater translocation of microbial antigens into the intestinal wall and portal circulation, inciting inflammation both locally and remotely.…”

Section: Discussionmentioning

confidence: 99%

“…Normally, these bacterial products are efficiently cleared by local immune defenses in the intestinal wall, lymph nodes, and liver. However, increased MT occurs in aged rodents (Ma et al 1992) and invertebrate models (Rera et al 2012) compared to younger groups. For example, fruit flies with impaired intestinal barrier function have reduced physical activity, and their loss of intestinal barrier function predicted imminent death (Rera et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…However, increased MT occurs in aged rodents (Ma et al 1992) and invertebrate models (Rera et al 2012) compared to younger groups. For example, fruit flies with impaired intestinal barrier function have reduced physical activity, and their loss of intestinal barrier function predicted imminent death (Rera et al, 2012). Recent studies have documented that aged people also have greater MT (Ghosh et al, 2014), and that even in healthy older people, MT specifically relates to physical function indices (Stehle et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Microbial translocation and skeletal muscle in young and old vervet monkeys

Kavanagh

Brown

Davis

et al. 2016

AGE

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Intestinal barrier dysfunction leads to microbial translocation (MT) and inflammation in vertebrate and invertebrate animal models. Age is recently recognized as a factor leading to MT, and in some human and animal model studies, MT was associated with physical function. We evaluated sarcopenia, inflammation, MT biomarkers, and muscle insulin sensitivity in healthy female vervet monkeys (6-27 years old). Monkeys were fed consistent diets and had large and varied environments to facilitate physical activity, and stable social conditions. Aging led to sarcopenia as indicated by reduced walking speeds and muscle mass, but general metabolic health was similar in older monkeys (n = 25) as compared to younger ones (n = 26). When older monkeys were physically active, their MT burden approximated that in young monkeys; however, when older monkeys were sedentary, MT burden was dramatically increased. MT levels were positively associated with inflammatory burden and negatively associated with skeletal muscle insulin sensitivity. Time spent being active was positively associated with insulin sensitivity as expected, but this relationship was specifically modified by the individual monkey's MT, not inflammatory burden. Our data supports clinical observations that MT interacts with physical function as a factor in healthy aging.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Microbial translocation and skeletal muscle in young and old vervet monkeys

Kavanagh

Brown

Davis

et al. 2016

AGE

View full text Add to dashboard Cite

show abstract

“…This gap is due in part to the difficulty of measuring causes of mortality in the standard animal models in aging studies. For example, age‐related morbidity and causes of mortality in the commonly studied models of aging range from the not well understood (and often not studied) in mice (Simms & Berg, 1957; Snyder, Ward & Treuting, 2016), to the poorly understood in flies and worms (but see Herndon et al., 2002; Rera, Clark & Walker, 2012), to nonexistent in yeast. In addition, many diseases important to human aging (e.g., cardiovascular disease and dementia) do not develop spontaneously in our commonly studied model organisms.…”

Section: Introductionmentioning

confidence: 99%

The companion dog as a model for human aging and mortality

et al. 2018

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SummaryAround the world, human populations have experienced large increases in average lifespan over the last 150 years, and while individuals are living longer, they are spending more years of life with multiple chronic morbidities. Researchers have used numerous laboratory animal models to understand the biological and environmental factors that influence aging, morbidity, and longevity. However, the most commonly studied animal species, laboratory mice and rats, do not experience environmental conditions similar to those to which humans are exposed, nor do we often diagnose them with many of the naturally occurring pathologies seen in humans. Recently, the companion dog has been proposed as a powerful model to better understand the genetic and environmental determinants of morbidity and mortality in humans. However, it is not known to what extent the age‐related dynamics of morbidity, comorbidity, and mortality are shared between humans and dogs. Here, we present the first large‐scale comparison of human and canine patterns of age‐specific morbidity and mortality. We find that many chronic conditions that commonly occur in human populations (obesity, arthritis, hypothyroidism, and diabetes), and which are associated with comorbidities, are also associated with similarly high levels of comorbidity in companion dogs. We also find significant similarities in the effect of age on disease risk in humans and dogs, with neoplastic, congenital, and metabolic causes of death showing similar age trajectories between the two species. Overall, our study suggests that the companion dog may be an ideal translational model to study the many complex facets of human morbidity and mortality.

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Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype

Liang,

Pan,

Yin

et al. 2023

Advanced Science

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The essential branched‐chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs’ full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence‐associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation‐related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age‐related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age‐related and inflammatory diseases.

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Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila

Cited by 520 publications

References 41 publications

Microbial translocation and skeletal muscle in young and old vervet monkeys

Microbial translocation and skeletal muscle in young and old vervet monkeys

The companion dog as a model for human aging and mortality

Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype

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