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.