Animal models of frailty: current applications in clinical research

Kane, Alice E.; Hilmer, Sarah N.; Mach, John; Mitchell, Sarah J.; Cabo, Rafael de; Howlett, Susan E.

doi:10.2147/cia.s105714

Cited by 50 publications

(35 citation statements)

References 62 publications

(104 reference statements)

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“…In clinical gerontology two major tools were developed to evaluate frailty in elderly: the phenotype model and FI (reviewed in [17]). The phenotype model describes frailty as a phenotype that can be scored using 5 criteria of patient's physical performance [18].…”

Section: Discussionmentioning

confidence: 99%

Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice

Antoch

Wrobel

Kuropatwinski

et al. 2017

Aging

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The development of healthspan-extending pharmaceuticals requires quantitative estimation of age-related progressive physiological decline. In humans, individual health status can be quantitatively assessed by means of a frailty index (FI), a parameter which reflects the scale of accumulation of age-related deficits. However, adaptation of this methodology to animal models is a challenging task since it includes multiple subjective parameters. Here we report a development of a quantitative non-invasive procedure to estimate biological age of an individual animal by creating physiological frailty index (PFI). We demonstrated the dynamics of PFI increase during chronological aging of male and female NIH Swiss mice. We also demonstrated acceleration of growth of PFI in animals placed on a high fat diet, reflecting aging acceleration by obesity and provide a tool for its quantitative assessment. Additionally, we showed that PFI could reveal anti-aging effect of mTOR inhibitor rapatar (bioavailable formulation of rapamycin) prior to registration of its effects on longevity. PFI revealed substantial sex-related differences in normal chronological aging and in the efficacy of detrimental (high fat diet) or beneficial (rapatar) aging modulatory factors. Together, these data introduce PFI as a reliable, non-invasive, quantitative tool suitable for testing potential anti-aging pharmaceuticals in pre-clinical studies.

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Section: Discussionmentioning

confidence: 99%

Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice

Antoch

Wrobel

Kuropatwinski

et al. 2017

Aging

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“…mice (39), perhaps the most widely used and established mouse model for frailty (40). Together, these observations suggest an important intersection between mitophagy, inflammasome activation, and the prevention of age-associated impairment.…”

Section: Mitochondrial Dna and Agingmentioning

confidence: 91%

The role of mitochondria in aging

Jang

Blum

Liu

et al. 2018

Journal of Clinical Investigation

316

241

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The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.

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“…The constellation of enhanced oxidative stress and reduced cell survival punctuates aging in multiple tissue beds. IL10‐deficient mice are a well‐accepted model of frailty that permits the interrogation of organ‐specific consequences of the chronic inflammatory frail state (Kane et al, 2016; Westbrook et al, 2017). We show here that late‐onset alveolar enlargement is a feature of this frailty model potentially reconciling a known systemic phenotype of aging with acquired lung disease.…”

Section: Discussionmentioning

confidence: 99%

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung

et al. 2020

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The connection between aging‐related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10‐deficient murine lung, a model of accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle‐aged (12 months old) and aged (20–22 months old) IL10‐deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild‐type (WT) controls, the IL10‐deficient lungs from young (4‐month‐old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10‐deficient milieu. Lung macrophages were increased in the aged IL10‐deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2‐polarized bone marrow‐derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10‐deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage‐mediated alveolar epithelial cell survival and B‐cell survival within tertiary lymphoid structures.

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Animal models of frailty: current applications in clinical research

Cited by 50 publications

References 62 publications

Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice

Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice

The role of mitochondria in aging

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung

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