Interventions for Frailty and Preventing the Development of Frailty

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Frailty represents a clinical state of highest vulnerability to adverse outcomes and mortality in older adults, making the development of specific strategies to prevent and treat frailty of utmost importance to expand and support healthy aging.  Although considerable progress has been made in the last decade regarding potential underlying biology of frailty (e.g., chronic inflammation, mitochondrial dysfunction), the exact etiology of frailty remains unknown.  Therefore, instead of treating frailty-causing biology, intervention efforts so far have largely been directed toward improving conditions that are believed to contribute to clinical manifestations of frailty such as sarcopenia and undernutrition.  In this arena, three major types of intervention have been attempted: (1) health behavior intervention; (2) individually-tailored geriatric care models; and (3) pharmacological intervention.

(1) Health Behavior Intervention.  Exercises, nutritional intervention, and multicomponent interventions that combine both exercise and nutrition are the most common.  Exercise.  Although both observational and experimental evidence exist on the benefits of exercise for improving health outcomes of older adults (Theo et al., 2011), it is important to note that very few studies have directly evaluated the impact of exercise intervention on frailty itself other than its components or physical function in general (Puts et al., 2017).  Among the five trials where frailty was measured by the physical frailty phenotype, older adults receiving exercise intervention focusing specifically on flexibility, balance, resistance, and endurance training showed improvement in frailty score (Cesari et al., 2015; Nagai et al., 2018, Ng et al., 2015), or reversal of frailty status (Kim et al., 2015; Chen et al., 2019).

Nutrition.  A review by Manal et al., 2015 summarized findings of four types of nutritional intervention: specific nutritional supplement formula; daily food fortification with protein supplement; nutritional education and counseling; and supplementation of micronutrients including vitamin D, omega three fatty acids; and multivitamin.  Frequently assessed outcomes include nutritional status and physical function, and some included physical activity.  The results have been mixed.  For example, food fortification (Smoliner et al., 2008), multinutrient supplementation (Fiatarone et al., 1994), and Vitamin D (Latham et al., 2003) showed no significant effect; while other studies of nutritional supplementation reported reversal of weight loss and improved nutritional status, but not functional outcomes such as grip strength.  Nutritional advice and counseling (Rydwik et al., 2010; Lammes et al., 2012) improved frailty status only among older adults at risk for malnutrition (Nykänen et al., 2014).  However, it is important to note that none of these studies used any of the modern frailty instruments such as the physical frailty phenotype.

Multimodal Intervention.  Because of the likely multifactorial etiology underlying frailty, interventions combining exercise, behavioral therapy, nutrition, and cognitive training have also been tested.  In three studies, the combination of exercise and nutrition intervention resulted in frailty status improvement (Kim et al., 2015; Tarazona-Santabalbina et al., 2015) or reduction in pre-frailty-to-frailty transition (Serra-Prat et al., 2017).   Most recently, a combination of nutritional supplementation, physical training, and cognitive training was tested in a 6-month randomized controlled trial in community-dwelling prefrail and frail older adults in Singapore (Ng et al., 2015).  It was found to improve frailty status in groups receiving each treatment alone as well as the group receiving all three at 3 months and 6 months, and the improvement persisted 6 months after treatment cessation (Li et al., 2010).

(2) Individually-Tailored Geriatric Care Models.  Instead of identifying a specific intervention or combinations of intervention that are uniformly efficacious for all frail older adults, individually tailored interventions based on impairments identified by the comprehensive geriatric assessment (CGA) have received growing attention. While evidence on the effectiveness of CGA in preventing functional decline is mixed in the general population, some have argued that the value of CGA could be greater in frail older adults at high risk for functional decline. To test this hypothesis, Li et al.  conducted a randomized controlled trial among pre-frail or frail community-dwelling older adults to assess the effectiveness of interventions prescribed on an individual basis by geriatricians based on the results of CGA.  Their study showed a positive but not significant effect in improving the frailty status. A recent study in a sample of mostly frail older adults with multimorbidity and high healthcare utilization found that the group who received CGA-based care and tailored interventions (e.g., reduction of polypharmacy, advice on exercise or diet, provision of adaptive equipment, and increased social support) in addition to usual care had lower mortality and prevalence of frailty at 24 months than those of the group receiving usual care (Mazya et al., 2019).

(3) Pharmacological Interventions.  In addition to non-pharmacological interventions, a recent review on the effects of pharmacological interventions in older frail adults found that the use of alfacalcidol (a vitamin D analog), teriparatide (an anabolic parathyroid hormone fragment), piroxicam (a nonsteroidal anti-inflammatory drug), testosterone (an anabolic steroid), recombinant human chorionic gonadotropin (rHCG), or capromorelin (a growth hormone secretagogue) was associated with improved frailty components including muscle strength (alfacalcidol or testosterone), body weight (testosterone, capromorelin, or rHCG), and fatigue (piroxicam) (Pazan et al., 2020).  Only one trial used the physical frailty phenotype to measure frailty in a study of the effect of 12-24-month testosterone supplementation in men and found no treatment effect on the frailty status (Kenny et al., 2010).

In summary, while there is no magic pill for treating frailty, intervention efforts so far have largely focused on treating symptoms of frailty via behavioral interventions including exercise and diet.  Pharmacological interventions on the other hand have been single-system focused with two primary targets: inflammation and anabolic hormones.  Given that frailty is theoretically defined as a syndrome of multisystem dysregulation, it raises the question of whether interventions designed to target the phenotypic components of frailty such as muscle weakness and malnutrition or a single-system focused one deficit/one therapy model (Cappola et al., 2008) in the case of hormonal therapy is sufficient for addressing or alleviating the root cause(s) of frailty.  As the pursuit of specific biological driver(s) of the multisystemic dysregulation continues, it may be more fruitful to direct intervention efforts toward better management of frail older adults through minimizing aggravating factors such as polypharmacy, environmental hazards (e.g., fall prevention), and discontinuum of care.

Epidemiology

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With such a profound impact on health, frailty is a growing concern in our aging population. Approximately 8.5% of the global population is 65 years old or older, and this percentage is projected to increase to nearly 17% by 2050

With such a profound impact on health, frailty is a growing concern in our aging population. Approximately 8.5% of the global population is 65 years old or older, and this percentage is projected to increase to nearly 17% by 2050 (He et al., 2016).  Using a variety of assessments, estimates of prevalence of frailty among older adults range from 4% to 59% of ambulatory adults (Collard et al., 2012).  Considerable variability in frailty prevalence has also been reported even restricting only to the most commonly used assessment method, the physical frailty phenotype (PFP), with estimates ranging from 4% to 17%. A 2015 study in a U.S. nationally representative sample, there National Health and Aging Trends Study (NHATS), found that 15.3% of non-institutionalized adults ages 65 and older were frail using the PFP (Bandeen-Roche et al., 2015).  Expected increases in frailty prevalence with age were observed: in NHATS, the prevalence ranged from 8.9% of those between 65 and 70 years old to 37.9% of those over 90 (Bandeen-Roche et al., 2015).

There also are major disparities in frailty prevalence by gender and especially by race/ethnicity and socioeconomic status.  Frailty is more common in women than in men (17.2% vs. 12.9%), in African Americans compared to non-Hispanic whites (22.9% vs. 13.8%), in Hispanic Americans compared to non-Hispanic whites (24.6% vs. 13.8%), and in lower income compared to higher income groups (25.8% vs. 5.9%) (Bandeen-Roche et al., 2015). Based on a recent follow up study, the disparity by race/ethnicity appears robust: Disease burden and BMI, which have been found to partially explain racial/ethnic disparity in health, do not explain racial/ethnic disparities in frailty.  The black-white disparities, moreover, are not restricted to low income groups (Usher et al., 2020).

According to a recent review, the global incidence of frailty was 40.0 cases per 1,000 person-years when using the PFP. The incidence was generally higher when using alternative assessment methods including the Deficit Accumulative Index (DAI; Ofori-Asenseo et al., 2019).  The incidence rate was also higher in women than in men (44.8 vs. 24.3 cases per 1,000 person-years).

Both cross-sectional and prospective studies have demonstrated a strong relationship between frailty and the development of disability, other geriatric syndromes such as falls, delirium, incontinence, and mild cognitive impairment, risk of hospitalization (Vermeiren et al., 2016; Fried et al., 2001; Bandeen-Roche et al., 2006), and longer inpatient care after procedures (Garoznik et al., 2012; Joseph et al. 2014; Juma et al.,2016; Makary et al., 2010; Maxwell et al., 2019; McAdams-DeMarco et al., 2013). Physically frail older adults are at increased risk of dying when compared to robust peers with hazard ratios varying between 1.2 and 6.0 (Chang & Lin, 2015; Shamliyan et al., 2013.) A meta-analysis of frailty, assessed with the DAI, reported that higher frailty index scores were associated with higher mortality risk (Kojima et al., 2018).  A similar analyses use the self-reported FRAIL Scale to define frailty found an association with increased risk of mortality (Kojima, 2018).

Epidemiological studies also have documented cross-sectional and longitudinal associations of frailty with markers of impaired physiology, including inflammatory cytokines (Soysal et al., 2016), immune factors (Leng & Margolick, 2020), serum micronutrients (Ju et al., 2018; Semba et al., 2006), sex hormones (Carcaillon et al., 2012; Cawthon et al., 2009), and metabolic biomarkers (Perez-Tasigchana et al., 2017). Measures of systemic (Bandeen-Roche et al., 2009) and multisystemic dysregulation (Fried et al., 2009; Gross et al., 2020) also have been implicated. Comorbidity (Weiss, 2011), sleep impairment (Pourmotabbed et al., 2020), and sensory impairments (Kamil et al., 2014; Swenor et al., 2020) also have been implicated as heightening frailty risk. Physical activity and BMI likewise are potential determinants (Kehler & Theou, 2019; Rietman et al., 2018). Their consideration vis-a-vis the PFP is complicated, however, because measures of these are incorporated the PFP assessment.

Frailty, therefore, is a major public health concern with substantial implications for the health and well-being of the older population. Studies identifying evidence of physiological dysregulation underlying frailty offer clues into potential strategies for prevention and slowing of frailty onset. Work to further develop this evidence and then the public health approaches to compress frailty and morbidity (Fries, 1980) into as narrow a span of end-life as possible are urgently needed. Implications may be exacerbated for Black and Hispanic Americans and for older adults who have experienced socioeconomic disadvantage. Further work to delineate and address mechanisms at work also is urgently needed.