Inflammation, Coagulation, and the Pathway to Frailty

Kanapuru, Bindu; Ershler, William B.

doi:10.1016/j.amjmed.2009.01.030

Cited by 135 publications

(110 citation statements)

References 98 publications

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“…Hallmarks of inflammation, including elevated IL-6, TNF-α, and immune cell chemokines, are associated with dementias (2), depression (3), atherosclerosis (4)(5)(6)(7)(8), cancers (9)(10)(11), diabetes (12)(13)(14), and mortality (2,15,16). Inflammation is perhaps the most important physiologic correlate of the age-related frailty syndrome (17)(18)(19)(20), which includes heightened vulnerability to stresses (e.g., surgery, infection, or trauma), coupled with muscle wasting (sarcopenia) and cachexia/fat tissue loss, all of which become increasingly common in old age (17)(18)(19)(21)(22)(23)(24)(25)(26)(27)(28)(29). Frailty predisposes to chronic disease, loss of independence, and mortality and greatly increases health costs (25,27).…”

Section: Introductionmentioning

confidence: 99%

Cellular senescence and the senescent secretory phenotype: therapeutic opportunities

Tchkonia¹,

Zhu²,

Deursen³

et al. 2013

J. Clin. Invest.

1,410

1,251

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Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions.

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Section: Introductionmentioning

confidence: 99%

Cellular senescence and the senescent secretory phenotype: therapeutic opportunities

Tchkonia¹,

Zhu²,

Deursen³

et al. 2013

J. Clin. Invest.

1,410

1,251

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“…3,5 In cross-sectional settings, or prospectively in later life, frailty has been associated with both clinical and subclinical cardiovascular disease (CVD). [11][12][13] Accelerated cardiovascular ageing 14 could be one explanation for the proposed relationship between frailty and CVD and also shared biological alterations, such as lowgrade inflammation, 15 may have a role. We have speculated earlier that development of frailty and weight loss therefore could also explain the 'obesity paradox' 16 -better prognosis among older people with overweight or obesity.…”

Section: Introductionmentioning

confidence: 99%

Association of midlife obesity and cardiovascular risk with old age frailty: a 26-year follow-up of initially healthy men

et al. 2012

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OBJECTIVE AND HYPOTHESIS:To investigate whether old age frailty is predicted by midlife overweight/obesity and cardiovascular disease (CVD) risk. DESIGN: Longitudinal observational study (the Helsinki Businessmen Study). SUBJECTS: In their midlife in 1974, 1815 initially healthy men (mean age 47 years) were clinically investigated, whereupon their weight status (normal weighto25 kg m À 2 , overweight 25pbody mass index o30 kg m À 2 and obese X30 kg m À 2 ), CVD risk factors and a composite risk score (%) of coronary artery disease (CAD) were assessed. After a 26-year follow-up in 2000, when 425 men had died, the frailty status of survivors (80.9%, n ¼ 1125, mean age 73 years) was assessed using a postal questionnaire including the RAND-36/SF-36 instrument. Phenotypic criteria were used to define frailty, and according to these criteria, 40.0% (n ¼ 450), 50.4% (n ¼ 567) and 9.6% (n ¼ 108) were classified as not frail, prefrail and frail, respectively. Risks are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Compared with normal weight, the development of frailty was significantly higher among those men who were overweight or obese in midlife, with fully adjusted ORs (95% CI) of 2.06 (1.21-3.52) and 5.41 (1.94-15.1), respectively. Even the development of prefrailty was significantly increased with midlife overweight (OR 1.39; 95% CI, 1.03-1.87) and obesity (OR 2.96; 95% CI,). Age-adjusted composite CAD score in midlife predicted similarly 26-year total mortality (OR per 1% increase:1.16; 95% CI, 1.08-1.24) and development of frailty (OR 1.16; 95% CI, 1.02-1.33). CONCLUSION: Overweight/obesity and higher CAD risk in midlife were associated with frailty 26 years later. Preventing old age frailty should be recognized as an important goal of obesity and CVD risk control.

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“…Despite recent advances in frailty research in human cohorts, the mechanisms that mediate SM decline and adverse outcomes in frailty remain unclear (Kanapuru and Ershler 2009). The homozygous interleukin-10 null, B6.129P2-IL10 ™/Cgn /J (IL10 ™/™ ) mouse has been proposed as a model to study the biology linking chronic inflammation and frailty (Walston et al 2008) given that they, like frail humans, develop elevated serum interleukin-6 (IL6), muscle weakness, and higher mortality compared to age-matched C57BL/6J (B6) controls (Walston et al 2008;Ko et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle ATP kinetics are impaired in frail mice

Akki

Yang

Gupta

et al. 2013

AGE

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The interleukin-10 knockout mouse (IL10 tm/tm ) has been proposed as a model for human frailty, a geriatric syndrome characterized by skeletal muscle (SM) weakness, because it develops an age-related decline in SM strength compared to control (C57BL/6J) mice. Compromised energy metabolism and energy deprivation appear to play a central role in muscle weakness in metabolic myopathies and muscular dystrophies. Nonetheless, it is not known whether SM energy metabolism is altered in frailty. A combination of in vivo 31 P nuclear magnetic resonance experiments and biochemical assays was used to measure high-energy phosphate concentrations, the rate of ATP synthesis via creatine kinase (CK), the primary energy reserve reaction in SM, as well as the unidirectional rates of ATP synthesis from inorganic phosphate (P i ) in hind limb SM of 92-week-old control (n=7) and IL10 tm/tm (n=6) mice. SM Phosphocreatine (20.2±2.3 vs. 16.8± 2.3 μmol/g, control vs. IL10 tm/tm , p<0.05), ATP flux via CK (5.0±0.9 vs. 3.1±1.1 μmol/g/s, p<0.01), ATP synthesis from inorganic phosphate (P i →ATP) (0.58±0.3 vs. 0.26±0.2 μmol/g/s, p<0.05) and the free energy released from ATP hydrolysis (ΔG ∼ATP ) were significantly lower and [P i ] (2.8±1.0 vs. 5.3± 2.0 μmol/g, control vs. IL10 tm/tm , p<0.05) markedly higher in IL10 tm/tm than in control mice. These observations demonstrate that, despite normal in vitro metabolic enzyme activities, in vivo SM ATP kinetics, high-energy phosphate levels and energy release from ATP hydrolysis are reduced and inorganic phosphate is elevated in a murine model of frailty. These observations do not prove, but are consistent with the premise, that energetic abnormalities may contribute metabolically to SM weakness in this geriatric syndrome.

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Inflammation, Coagulation, and the Pathway to Frailty

Cited by 135 publications

References 98 publications

Cellular senescence and the senescent secretory phenotype: therapeutic opportunities

Cellular senescence and the senescent secretory phenotype: therapeutic opportunities

Association of midlife obesity and cardiovascular risk with old age frailty: a 26-year follow-up of initially healthy men

Skeletal muscle ATP kinetics are impaired in frail mice

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