Mitochondrial Dysfunction and Frailty

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mitochondriaOne major feature of physical frailty is the lack of ‘energy’ often described fatigue by frail older adults. Early hypotheses of the underlying causes of physical frailty included the proposal that mitochondrial dysfunction led to low levels of energy production and ultimately to clinical features such as fatigue and low energy/activity levels (Wallace, 2011; Loeb et al., 2005; Wallace, 2010; Wallace 2005; Wallace, 2001). Over the past several years, studies into the biology of frailty have indeed identified features of mitochondrial decline that may ultimately contribute to physical frailty. Mitochondria are the cell’s power houses, generating energy in a highly charged process, called oxidative phosphorylation, which transfers electrons from oxygen to make ATP. ATP is an energy source that is utilized for almost all cellular activities. The process of making ATP creates reactive oxygen species (ROS), which can damage cellular structures if not quickly neutralized (Conley et al., 2007).

With aging, there is an accumulation of damaged mitochondria that, once established, is thought to be irreversible. Recently, several studies have shown the presence of mitochondrial changes that predate the accumulation of clearly damaged mitochondria by almost a decade (Amara et al., 2007; Skulachev, 2006; Bratic & Trifunovic, 2010; Dirks et al., 2006; Taneike et al., 2010). These studies have demonstrated that such changes are associated with a functional reduction in mitochondrial efficiency in otherwise healthy people in their sixties (Amara et al., 2007).  There is a vicious cycle in the deterioration of mitochondrial function with increasing age (Bua et al., 2006; Greco et al., 2003; Hutter et al., 2004; Mogensen et al., 2006).  Aging is associated with increased ROS and reduced ATP production. Higher rates of ROS production lead to mitochondrial damage and further lower ATP production, eventually triggering pathways that cause mitochondrial self-destruction through a pathway called mitophagy. (Lemasters, 2005; Garza-Lombó, et al., 2020; Vajapey et al., 2014). At the same time, the generation of new mitochondria is reduced because biogenesis and turnover are energy intensive, requiring a high capacity for ATP production.

Direct evidence that these changes in mitochondrial function with age result in clinical symptoms such as fatigue remains an important research goal. However, several studies have investigated the relationship between mitochondria and muscle function.  Mitochondrial energy production in response to skeletal muscle movement – that is the ability to sustain an increase in demand – declines during activity at a faster rate in frail compared to non-frail older adults (Varadhan et al, 2019; Lewsey et al., 2020). This suggests that frailty involves a reduced ability to generate energy when it is needed as a result of mitochondrial dysfunction.

Work in the IL-10 knockout mouse model of frailty also suggests a mitochondrial link to frailty. This mouse develops accelerated chronic inflammation, has lower ATP production at older ages compared to age-matched controls, and decreased ability to clear damaged mitochondria suggesting abnormally slow mitophagy and slow clearance of damaged mitochondria (Abadir et al., 2017; Akki et al., 2014).

Importantly, early changes in mitochondria are potentially reversible (Conley et al., 2013; Lumini et al., 2008; Conley et al., 2007), especially if identified at younger ages, and therefore might be a target for medical therapies designed to improve the health-span and prevent frailty in later life.

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.