On Frailty

“Health is life lived in the silence of the organs.”
– René Leriche
‍

In the US, the number of people alive aged 65 or older increased from 4.9 million (4.7% of the total U.S. population) in 1920 to 55.8 million (16.8%) in 2020. According to the American Census Bureau, this increase represents a growth rate of ~1,000%, almost five times that of the total population. Consequently, in 2020, about 1 in 6 people in the United States were aged 65 and over (against 1 in 20 In 1920). Most of the developed world has been undergoing a demographic transformation of similar astonishing proportions, prompting the International Monetary Fund (IMF) to describe the trend toward a much older populaton as a “population bomb.”

While this demographic shift is a testament to progress in healthcare, and a decrease in fertility rate, it also presents unique challenges, including the increasing prevalence of frailty among older adults. Why do some older people die in the face of heat waves and others do not? What has created the heightened risk of mortality from COVID-19 in some older people? While chronic diseases and other conditions can account for some of this vulnerability, frailty may be a big part of the answer. What is frailty? Where does it come from? Can it be understood and treated to allow not only longer but healthier life spans?

Frailty is considered a state of depleted reserve resulting in increased vulnerability to stressors. Frailty is a common clinical syndrome in older adults that increases the risk of poor health outcomes, including falls, incident disability, hospitalization, and death. While age is the main factor for the development of frailty, genetic components also play an essential role. As research progresses on the causes of frailty, surprising contributory factors have come to light including childhood experiences and socio-economic status.

The definition of frailty has evolved over the past 15 years. Here, we will focus on physical frailty instead of cognitive decline and detail two definitions that are used most often. They were expertly described and summarized in a Nature Aging article by Linda Fried from Columbia University.

Physical Frailty Phenotype (PFP)
This measure relies on a validated clinical presentation and well-established distinct clinical syndrome and pathophysiology, looking at weight loss, exhaustion, weakness, slowness, and lack of activity. More recent and surprising phenotypes like olfactory impairment are being added to this list. Physical frailty often presents without apparent clinical diseases or disability, but it can also co-occur with disease and disability. The frailty phenotype is an overall multi-system health assessment measuring a state of heightened vulnerability. According to this metric, the root cause of physical frailty is the dysregulation of key biological systems: stress response, metabolism, and muscle-skeletal systems. In her article, Fried uses the useful metaphor of physiological systems playing harmoniously like instruments in a symphony. Individual physiological systems decline in efficiency as the body ages and cell communications deteriorate. This creates a cacophony, precipitating the decline of individual systems and the whole organism.

Frailty Index (FI)
Technically, the Frailty Index is a ratio of the number of deficits an individual has accumulated divided by all measured deficits. These deficits include diseases, signs and symptoms, laboratory abnormalities, cognitive impairments, and disabilities in activities of daily living. It’s conceptually based on the clinical observation that multiple identified clinical problems in a patient create an aggregate risk of poor outcomes. Several frailty indices exist, including a clinical deficits frailty index (FI-CD) and a biomarker-based frailty index (FI-B).

These distinct frailty conceptualizations carry much of the same nomenclature and predict similar mortality and hospitalization risks. However, they denote different theories, etiologies and measures, and identify vastly different populations. Research has shown that of the people deemed frail by either measurement, a low percentage were deemed frail by both standards. About a third were classified as frail by the PFP, but not the FI, and about half were classified as frail by the FI, but not the PFP. Participants with greater disease burden were most likely to be characterized as being FI-frail, but not PFP-frail. The associations of frailty with age and mortality were stronger when the PFP rather than the FI measured frailty.

More importantly, the two standards recommend different targets of intervention. While one focuses on the accumulation of chronic or acute conditions, the other takes a more holistic approach to frailty and proposes treatment to the complex system rather than the defective parts. In both cases, thought, the recommendations are primarily behavioral interventions to improve physical activity or social engagement instead of pharmacological approaches. Interestingly, to date, drugs treating inflammation and anabolic hormones have been found to ameliorate partial aspects of frailty but have failed to address the overall syndrome. The best way to treat frailty at this point with clinical interventions is to better manage the frail by minimizing aggravating factors such as poor adherence and management of medications, environmental hazards, and discontinuities of care while optimizing healthy behaviors such as physical activity.

The consequences of frailty map clearly to the current challenges our aging societies already endure: increased cost and utilization of healthcare, strain on caregivers and family members, social isolation of older adults, and reduced quality of life. Aging is a societal, medical, psychological, and epidemiological subject more than just a biological one. As complex problems require complex solutions, and as the US and most of the developed world are expected to continue to grow older in the coming decades, innovations to attenuate the various ailments of old age will have to take center stage in the years to come. Pharmacological approaches alone won’t be sufficient to address frailty as one of the most common aspects of aging, but will put pressure on public health experts to work hand in hand with physiologists and geriatrics professionals to craft wide-ranging changes to how society supports and cares for the elderly.

– Jonathan Friedlander, PhD & Geoffrey W. Smith





Engineering Biology
Jacob Oppenheim, PhD, Entrepreneur-In-Residence at Digitalis Ventures, writes Engineering Biology at Digitalis Press:

This month, Jacob wrote about software as management technology: When you have a process, software routinizes it, enforces it, and enables scale and speed and breadth. We need common, reusable components to design these processes and to identify the common biological and digital primitives to build off of. Software sits atop these processes, reifies them, and enforces consistency, laying a foundation upon which a technological superstructure can be built.



First Five
First Five is our curated list of articles, studies, and publications for the month.

1/ Food for (bad) thought
A large Harvard study involving more than 30,000 people and published in JAMA Network showed that diet influenced the rate of depression. Recent experimental data suggests that artificial sweeteners elicit purinergic transmission in the brain, which may be involved in the genesis of depression. This study confirms that consuming some ultra-processed foods (UPF) correlates well with an increased risk of depression.

2/ More tips to avoid depression
On a similar topic, a Nature publication following almost 290,000 people over nine years outlined seven healthy lifestyle actions that should help keep depression at bay: moderate alcohol consumption, healthy diet, regular physical activity, healthy sleep, never smoking, low-to-moderate sedentary behavior, and frequent social connection. It’s nothing new, but having them confirmed and repeated is always helpful!

3/ One more tip: keep busy, keep happy
A massive Nature Medicine study conducted by scientists at UCL that followed 93,263 people aged 65 or over enrolled in longitudinal studies in 16 countries showed that having a hobby is linked to fewer depressive symptoms and higher levels of happiness, self-reported health, and life satisfaction in older adults!

4/ Just how many cells are in the human body?
A research group from McGill created a holistic quantitative framework for the cells of the human body to highlight large-scale patterns in cell biology and estimate the total number of cells. According to their publication in PNAS and their online human map, a stereotypical 70kg man has about 36 trillion cells, a 60kg woman has roughly 28 trillion cells, and a 10-year-old child has about 17 trillion cells.

5/ Learning with no brain
A recent Current Biology article changed what we thought we needed to be able to perform advanced learning. Even without a central brain, jellyfish can learn from past experiences like humans, mice, and flies. Scientists trained jellyfish to spot and dodge obstacles, shedding new light on the evolutionary roots of learning and memory.



Digitalis Commons
Catalyzing Health

Digitalis Commons is a non-profit organization that builds frontier-advancing, scalable solutions that have an outsized impact on important problems in health and health care.

Digitalis Commons’ partner ARPA-H announced the creation of ARPANET-H, a nationwide health innovation network.

The state of North Carolina has been piloting a large-scale program called Healthy Opportunities Pilots to test and evaluate the impact of providing select evidence-based, non-medical interventions related to housing, food, and transportation to high-needs Medicaid enrollees. The first recently published assessment showed that delivering fresh foods and non-medical services to low-income families positively impacts their physical and mental health.

‍