Frailty

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John E. Morley, MB, B.Ch,  St. Louis University, Division Of Geriatric Medicine, St. Louis, MO and St. Louis VA Medical Center, GRECC, St. Louis, MO, USA

This morning, I was according to Dr. Lunenfeld to talk on frailty, a talk I have never given before, so hopefully it will be of some use. 

I think when we think of frailty, the best way to start is to think of the story of Titonus and Aurora. Aurora was a goddess who had both a morning and an evening lover. Titonus was her morning lover but he did something for Aurora that was so magnificent, and the beauty of the story is you are never told what he did for Aurora, but he did it so well, that basically she did not want to lose him. So she went to her father, the god of gods, Zeus, and she said, daddy dearest, please, I need immortality for this gentleman - give him eternal life. Zeus is a doting father, he puts his hand in his pocket, throws out a thunderbolt and Titonus now has eternal life. The problem is, she forgot to ask for eternal youth. As the story goes, somewhere around about the age of 50, his libido started to fall off. By the time he was 70, there was a clear problem with potency. By the time he was 80, he walked with a stoop and was slow to get around and the story says by the time he reached 100, he had developed mild cognitive impairment and went around Aurora’s castle babbling incessantly. Aurora no longer loved Titonus and just wanted to get rid of him. Unfortunately, she could not kill him any more because he had immortality. One day, she heard the grasshoppers outside and she thought, what should I do, he is babbling all the time and she turned him into a grasshopper. And now when you hear the grasshoppers chirping all the time, it is just a group of old men babbling incessantly. 

And that is frailty or Titonism and you can see here the things that we think of as the normal physiology of aging that lead to frailty. The decline in vision, hearing and age-related memory disturbance, decline in sense of smell, we do not eat as much, we develop an anorexia of aging, we develop hypodipsia, our muscle mass and strength disappears, we decrease our VO2 max and we cannot perform as well, we lose our male hormones over time and we develop osteoporosis. These are the physiological changes of aging or the pre-frailty that all of us go through from the age of 50 onward.

The concept of frailty was perhaps first best elucidated in the modern literature by Bernard Isaacs in Birmingham, when he talked about the giants of geriatrics. These are the conditions that geriatricians deal with in the frail, older person, and they are instability, immobility, intellectual impairment and incontinence. Today, of course, what we would like to add to that is impotence of both hormones and male function, and those would be the five giants of geriatrics at this moment in time.

So many years ago, one of my fellows, Pakesh Norian, was looking at what decided in hospital how well you did and he decided that it really was how you functioned when you were over the age of 70 and he looked at the basic activities of daily living. These are the things we do every morning. When you get up in the morning, you transfer out of bed, you do not have to be able to walk because you can transfer to a wheelchair. If you are like me, you then run like mad to the toilet because otherwise you leave a little drop of urine behind. After you have toileted, we really hope you wash yourself and bathe. Having bathed, now for a long time I lived in Los Angeles and there you could walk out like you can in parts of Europe with no clothes on and it would not make any difference. But in St Louis, where I live now, they call the police when I do that, so you have to dress. After having dressed yourself, if you are really civilized, you sit down and eat breakfast. You then get in your car, you are halfway to work, your gastrocolic reflex kicks in and you have to go. But, because you have an intact sensorium, you know you do not want to leave anything behind in the car and so you control your continence and there is no little green thing left behind when you leave the car. These are the basic activities of daily living and what Dr. Norian showed very nicely is if you come into hospital and these are intact, your six-month mortality is about 18% to 19%. Still pretty high if you are 70; however, if you are lacking these, over half of these people die and if you are intact, you are unlikely to go to a nursing home in the next six months. If you are lacking them, you are very likely to finish up in a nursing home. So these very simple things, performed better than whether you had cancer, New York Heart Association stage four disease, no matter what disease you have, disease is not as good a predictor as these very simple things of frailty in the older person. This has been repeated since we did this originally. Now, most probably, 100 times in the literature, and it comes up the same way every time. The only good other predictor is nutritional status, which is perhaps best predicted in hospital by having a BMI of less than 21. So it is not how fat you are when you are old, but how skinny you are that decides how poorly you do over the age of 70.

So let us look at what happens. When we are young, we grow up and all of these things work well and they work better and better until we get to about the age of 20 to 25. Somewhere around the age of 30, we start to decline. We go down this steady decline until we reach about 100 and if we have a disease, we go down faster. If we do good things, such as do not smoke or as we get older start to exercise, we may push the curve up a little bit, but eventually we reach a frailty threshold where we basically no longer can do our activities of daily living and function well.

So what is frailty? For each of you in this audience, frailty I am sure is a slightly different thing. Every physician can recognize frailty. The problem we have is defining it. One of the better definitions in the literature is from Brown, who says “it occurs when there is diminished ability to carry out important, practical social activities of daily living.” That is nice, but difficult often to measure.

So recently in January, the National Institute of Aging held a consensus conference in Baltimore and they decided that for a working definition, they would use the Linda Fried and Anne Newman definition that was developed out of Johns Hopkins and Pittsburgh for frailty. This is an objective definition and it basically is, if you have weight loss, if you claim to be exhausted, if you have weakness as measured objectively by grip strength, if you have a slow walking speed and low physical activity, this is now considered to be the practical definition or objective definition of frailty. In the Freed studies, this occurs in about 7% of people and, as we might expect or as men we might hope, females actually have more frailty than males. So the good thing about being a male, while we all die earlier as we heard yesterday, we will actually live our lives with less frailty than the average female, so there are some positives about being males, not many.

So if we look at the effects of frailty, people who are frail have a decline in mobility, they have decreased social activity, then tend to become incontinent, because of the decline in mobility and other aspects of frailty, they have falls, they have osteopenia. You put all of this together, they develop hip fractures which can lead to a fear of falling and a decrease in mobility. Frailty puts us on this decline in function, leading to hospitalisation, institutionalisation and death.

That is the general outline of frailty. What are the causes of frailty? This very busy diagram points out to you that frailty has many causes. Frailty is caused by aging itself. It is caused by our inherent genetic makeup and there are very good studies coming out in centenarians now showing that some genes are protective. You certainly do not want to be born with an upper lipoprotein E4, for instance. The other thing is how well you are educated. Better-educated people develop frailty later and have less frailty than people who are not well educated. But anorexia, inactivity or lack of exercise, pain, depression, diabetes, delirium, atherosclerosis, sarcopenia, weight loss, low body weight, dehydration, heart disease, stroke, cognitive impairment, processing speed and delirium are all part of the frailty cascade and I could add to this if I had space on the slide most probably another 100 things. There are many, many things that lead to frailty which is why it is so often difficult often to reverse.

Now this is a good poem. It came from 1947 from Dr. Richard Asher and it points out what happens to the older person when they come to hospital:
“Look at the patient lying long in bed.
What a pathetic picture he makes.
The blood popping in his veins, deep vein thrombosis.
The lime draining from his bones, osteoporosis.
The scybola stacking up in his colon, constipation.
The flesh rotting from his seat, pressure ulcers.
The urine leaking from his distended bladder, incontinence.
And the spirit evaporating from his soul, depression.
Teach us to live that we may dread unnecessary time in bed.
Get people up and we may save our patients from an early grave.”
We have, I think, in the last decade become very aware that bed time is bad time in hospitals for older people.

This is just one example of how you become frail. These are all the Monet paintings, the bridge across Giverny, and you can see early in his life, he could paint the bridge and you could see the bridge very clearly. As he got older, the bridge virtually disappeared. What had happened to Monet? He had developed cataracts. Imagine seeing a bridge like that and then trying to find your food in the kitchen. There is almost no hope. So simple things, such as development of cataracts, if they are not fixed, can lead to frailty.

One of my favorite patients as shown here, I am looking after its anonymity much better than I do most patients’. This patient was the companion of an 84-year-old. The 84-year-old died, the patient became very upset, started scratching the children in the house, stopped eating, became very malnourished, started becoming incontinent all over the house and the family, being worried about the patient, called in the veterinarian. The veterinarian took one look at the patient and said, I know the diagnosis is senile dementia and he decided he would carry out the next day what he thought was the appropriate therapy, which was euthanasia. Fortunately for the patient, when the veterinarian went home that night, he talked to his wife, his wife had no medical backup at all and so basically she said, wait, there is another possible diagnosis. She came out the next day, handheld the paws of the patient, talked gently to the patient, handfed the patient and what you see here three months later, after excellent psychotherapy for depression, is one big, fat cat. Depression is perhaps one of the most major causes in our older patients of developing frailty and it is often not seen by physicians.

Obviously, the other thing that happens to us as we get older is we develop a lack of good thinking skills – cognitive impairment. We are now very aware that a condition called mild cognitive impairment has become extraordinarily important in setting people up when they come into hospital to develop frailty and have poor outcomes. Falstein’s many mental status does not pick up mild cognitive impairment and because of this, at St Louis University, we have developed a mental status examination which takes about six minutes to do that will pick up mild cognitive impairment, as well as dementia. This has now been validated by Dr. Turiq and is actually an excellent way to look for the people who are at greater risk when they come into hospital and are going to have surgery, for instance, or have had a hip fracture of having poor outcomes during the surgery.

But other things can also cause frailty. We heard this morning in the first frailty lecture about the metabolic syndrome or the deadly quintet first described by Camus and popularized by Reaven much later. This is the condition where lack of exercise, a couch potato, an over-eating beast of visceral obesity. With visceral obesity, we get an increase in tumenacrosus factor alpha, an increase in leptin and these people tend to have lower adiponectins which appear to be key to the insulin-resistance syndrome. This leads to insulin-resistance with hypoinsulin anemia. We get diabetes, hypertension, hyperuricemia, abnormalities in farting and limpid abnormalities, particularly hypertriglyceridemia and a decrease in and changes to the small dense LDL. But the metabolic syndrome we now know is also associated with myosteatosis, which is the infiltration of fat into muscle and cognitive impairment. When we put this all together, clearly people with a metabolic syndrome go on to develop frailty.

In fact, there is good data showing that diabetes is associated with frailty. Diabetics have poorer functional status, they have more injurious falls, they have impaired cognition - this is from the Mexico City data with Geraldo Rodrigues Saldana in our group, the Pacquid study in France, the Sinclair Aware study in Wales and our African-American study in St Louis. Alan Sinclair in England actually looked at diabetics and looked at the social activity and he found that diabetics read less, garden less, use the telephone less, write letters less and were less likely to go out socially. 

Another condition strongly associated with frailty, we are recognizing now that anemia, and this is hemoglobin below 12, are strongly associated with frailty. A number of studies in the last year have shown this. Decline in function, falls, mobility impairment, fatigue, orthostasis, myocardial infarction, all leading to mortality. This has given risen to the fact that many people are now treating frail people with arithraproetin or darbaproetin alpha in an attempt to reverse the frailty with some success.

We recognize that many of our patients need drugs, but we have a polypharmacy conundrum. Vincent van Gogh always painted his physician, Dr. Gachet, with a foxglove in his hand because Vincent had, in fact, epilepsy and he was being treated with digitalis leaves. What happened to van Gogh? He became a great painter because of the toxicity of his drug therapy. Here is Starry Night. Any of you who has seen someone with digoxin toxicity recognized that this is classical digoxin toxicity but, you know, if I am 80 and this happens to me, you will tell me I am hallucinating and I am crazy and there is no place for me and I will become frail. In a study we did where we reduced people on medications over the trend, we showed that we could reduce hospitalizations by one-third. We also reduced deaths by one-third and, in fact, every single death that occurred in the study was because the person made the mistake of going back to their physician who restarted the original drug that we had taken them off. You need to recognize that drugs are not always good for our older patients and can get us into problems.

What about Sarcopenia? First a new term coined by Rose Irvin Grosenberg in 1990, this is from the New Mexico Aging Process Study, where we showed with Rick Baumgartner a decline in muscle mass, both in men and women, and a decline in grip strength with aging. That is nothing new, but what Rick has led us in showing is that basically about half of the sarcopenic people with no muscle mass are also obese. 

So you see here from our studies that basically sarcopenia and sarcopenia obesity very common by the time you reach 80, about nearly half of the older males have either sarcopenia or sarcopenia obesity and recently in the New Mexico Aging Process Study, we found that obese sarcopenia is the best predictor of future disability and mortality, looked at longitudinally over a ten-year period. Recognizing that this combination of loss in muscle mass and obesity is worse than anything else.

All of us in this audience are very aware that multiple hormones can led to frailty, from testosterone, estrogen, vitamin D, growth hormone, DHEA, and they can lead to this through atheroma, cognitive decline, changes in muscle mass and osteoporosis.

We saw last night from Dr. Harman the longitudinal changes in testosterone. There are now four groups who have shown this clear decline in testosterone with aging. 

Rick Baumgartner now shows in the New Mexico Process Study that the single best predictor of muscle mass and a very good predictor of decline in grip strength is the three testosterone index. This has now been shown by many other groups, including Anne Kinney and the Rotterdam study, so it seems to be clear that testosterone plays a better role, but IGF-1 is also involved, as is physical activity and an energy intake.

In this study that Gary Withet and I did in Australia, we replaced a very low dose of andriol, testosterone andecanate, and we showed that there was a marked increase of a year in the increase in lean body mass and a decrease in fat mass. These were men who on the whole were not hypogonadal. They were older men with a physiological decline in testosterone and even in that group, you can change body composition.

Edith Sea and I many years ago showed that in a truly hypogonadal group, you can in fact improve grip strength. Studies from Urban and other people looking at truly hypogonadal patients again suggest an improvement with testosterone replacement of strength but only in hypogonadal males, not in the eugonadal males.

Testosterone has been shown to increase muscle size in both type 1 and type 2 fibres, it increases maximal muscle strength and leg power if you are hypogonadal, it enhances muscle synthesis but, most importantly, recently Shelley Bhasin has shown that testosterone increases satellite cell precursors and inhibits formation of the adipocyte precursor.

In our inner cities project with Doug Miller, we have shown that bioavailable testosterone is one of the best indicators of functional deterioration and in a small pilot study Bakhshi at the Medical College of Virginia has shown, in fact, that if you give testosterone back to men coming out of hospital, you get a marked improvement in functional index measure. This is functional status. If this can be repeated in other studies, the best use of testosterone is going to be in males coming out of hospital.

Vitamin D declines in aging even in sunny climates. This is a study that Mike Perry, Rick Baumgartner and I did in New Mexico where we show the decline in healthy people living in New Mexico, which has a very high sunlight exposure, over a 14-year period. Hypovitamin D is associated with declines in muscular strength and reported disability. Low vitamin D and high PTH are associated with sarcopenia, shown at the end of last year by the Dutch group. I think that was the Rotterdam study. Low vitamin D is an independent predictor for this and vitamin D supplementation with calcium appears to improve strength and performance but only in persons with low vitamin D.

What about growth hormone and frailty? The Rudman Study said it would cure us all but, in fact, this was most probably not reality. 

There is little data to support that growth hormone will do much more than improve weight gain and increase muscle mass, possibly increase type 2 fibres. It does not increase strength and long-term has produced side-effects. 

What about IGF-1. The studies by Nadia Rosenthal and her colleagues in Rome have shown that localized IGF-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle.

This is the future. Stem cell transplant to reverse the sarcopenia of aging. Ghrelin, a growth hormone-like releasing substance released from the stomach, enhances food intake and growth hormone. It also enhances memory. It is potentially one of the most exciting of the compounds we are looking at but, as a word of caution, MK-771, which worked through similar receptors, failed in a year-long study to produce significant effects in humans.

Steroid hormones decline with aging. 

The DHEA Age Study of Baulieu and his colleagues, published first in PNAS and then other parts of the archives in internal medicine, has failed to show an adequate effect of DHEA on anything. I think we need to recognize that you have to give enough DHEA to produce testosterone to get effects.

Rapidly, weight loss in older people leads to death. Many, many studies have shown this at this stage. 

This is from our nursing home study. If you lose weight in one thousand nursing home patients, 30% dead in six months. If you can gain weight back, only 10% will be dead. 

Cicero said, “I am grateful to old age because it has taken away my appetite and allowed me to spend more time in good conversation.” This is good, but not that good, because we now know that there is a clear anorexia of aging, it is a physiological anorexia of aging that causes weight loss when we are getting old. 

Release of cytokines causes anorexia, cognitive impairment, sickness behaviour, muscle wasting, decrease in oxygen retention, decrease in albumen synthesis, anemia and extermination of albumen from the intra-vascular spaces leading to a low albumen.

Cytokines associated with illness are a major cause of frailty. 

Recently we have shown that cytokines impair cognition by crossing the blood-vein barrier. 

Many studies on cytokines coming predominantly from Linda Fried’s group, Marco Bohaul and the Perionti Study in Italy have all shown that cytokines are strong predictors of frailty.

So, to conclude, how do we prevent or slow the onset of frailty. This is my pneumonic to do it. This is the frailty pneumonic. You want to maintain food intake, as Ruben Andress showed many years ago, basically it is better to be fat when you are old than to be skinny. Resistance exercise is absolutely key and most probably the most important thing you can do. You would like to prevent atherosclerosis. You want to stop isolation and the onset of depression. You want to limit pain because pain stops you functioning. You want to do tai chi or some other kind of balance exercises and, somewhat biasly, I would say you would like to check your testosterone on a regular basis, though I think all the data to prove that is not yet there.

Basically, this final schematic is just showing you what I have been trying to tell you: frailty is extraordinarily complex. It involves a variety of disease processes, decreased physical activity, changes in testosterone and cytokines. When we start to fall, we develop a fear of falling which stops us from having any activity. So over the lifespan as we get older, we decline in our function and we become frail, leading to functional impairment, fall fractures and institutionalization. I remind you again that the National Institute for Aging has done a Consensus Conference and suggested an objective definition for frailty. If you want to study this, if you are looking at hormone replacement, this is the definition you should be looking at and including in your studies.

Thank you all very much.