Clinical research overview

Frailty is a common and important geriatric syndrome characterized by age-associated declines in physiologic reserve and function across multiorgan systems, leading to increased vulnerability for adverse health outcomes. Two major frailty models have been described in the literature. The frailty phenotype defines frailty as a distinct clinical syndrome meeting three or more of five phenotypic criteria: weakness, slowness, low level of physical activity, self-reported exhaustion, and unintentional weight loss. The frailty index defines frailty as cumulative deficits identified in a comprehensive geriatric assessment. Significant progress has recently been made in understanding the pathogenesis of frailty. Chronic inflammation is likely a key pathophysiologic process that contributes to the frailty syndrome directly and indirectly through other intermediate physiologic systems, such as the musculoskeletal, endocrine, and hematologic systems. The complex multifactorial etiologies of frailty also include obesity and specific diseases. Major clinical applications include risk assessment and stratification. This can be applied to the elderly population in the community and in a variety of care settings. Frailty may also be useful for risk assessment in surgical patients and those with cardiovascular diseases, cancer, or human immunodeficiency virus infection, as well as for assessment of vaccine effectiveness in older adults. Currently, exercise and comprehensive geriatric interdisciplinary assessment and treatment are key interventions for frailty. As understanding of the biologic basis and complexity of frailty further improves, more effective and targeted interventional strategies and innovative geriatric-care models will likely be developed.

Owing to detrimental hazards and substantial healthcare burden and costs, hospitalisation of older people has become a major focus. Frailty has increasingly been recognised as an important predictor of hospitalisation. This study aims to identify studies on physical frailty as a predictor of hospitalisation risks and to pool the risk estimates among community-dwelling older people.

Most older individuals develop inflammageing, characterized by elevated blood inflammatory markers and high susceptibility to chronic morbidity, disability, frailty, and premature death. Mechanisms include genetic susceptibility, central obesity, increased gut permeability, microbiota changes, cellular senescence, NLRP3 inflammasome activation, oxidative stress from dysfunctional mitochondria, immune dysregulation, and chronic infections. Inflammageing constitutes a risk factor for cardiovascular disease, chronic kidney disease, diabetes, cancer, depression, dementia, and sarcopenia. Whether inflammation modulation beneficially affects non-CVD health remains controversial, particularly in older multimorbid patients. Hypothesized mechanisms involve growth factor inhibition, increased catabolism, and homeostatic signalling interference.

Human aging is characterized by chronic, low-grade inflammation termed inflammaging, a highly significant risk factor for morbidity and mortality in elderly populations. Most age-related diseases share inflammatory pathogenesis. Identifying pathways controlling age-related inflammation across multiple systems is important for determining whether treatments modulating inflammaging may benefit older people. This report documents outcomes from the Advances in Gerosciences meeting inflammation session held at NIH/NIA.

No therapy-related treatment-emergent serious adverse events occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in 200M- or placebo groups. Female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both 100M- (p < .0001) and 200M-groups (p = .002) and between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy.

No treatment emergent serious adverse events occurred. In all treatment groups, 6-minute walk distance increased at 3 months (p = .02) and 6 months (p = .001) and TNF-α levels decreased at 6 months (p < .0001). The 100-million dose showed the best improvement in all parameters, except TNF-α, which improved in both 100- and 200-million groups (p = .0001 each). The 100-million cell-dose group showed significant improvements in the physical component of the SF-36 quality of life assessment at all time points relative to baseline.