Cyberfriends: The help you're looking for is probably here.

Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at myphysicians.com, and another at www.afraidtoask.com.

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With one of four large boxes of "Pathguy" replies.

I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

My home page
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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I presently have no sponsor.

This page was last updated February 6, 2006.

During the ten years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!

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The span of our life is seventy years, perhaps in strength even eighty,
Yet the sum of them is but labor and sorrow, for they pass away quickly and we are gone.

-- Psalm 90: 10.

I grow old ever learning many things.

-- Solon

Someone asked Sophocles [when he was 90], "How do you feel now about sex? Are you still able to have a woman?" He replied, "Hush, man; most gladly indeed am I rid of it all, as though I had escaped from a mad and savage master."

-- Plato's Republic

Old people like to give good advice, as solace for no longer being able to provide bad examples.

-- de la Rochefoucauld

Age does not bring wisdom. Often it merely changes simple stupidity into arrogant conceit. Its only advantage is that it spans change. A young person sees the world as a still picture, immutable. An old person knows that it is a moving picture, forever changing.

-- Robert Heinlein

Not so much to add years to life, as to add life to years.

-- Geriatrician's motto

May you live as long as you want to. May you want to as long as you live.

-- Traditional blessing

LEARNING OBJECTIVES

Tell what we know about the fundamental biology of aging. Distinguish "primary aging" and "secondary aging". Explain why we think senescence is inevitable. Describe current ideas about why this happens. Describe the Hayflick phenomenon of replicative senescence, and current thinking about its cause.

Tell how old people's cells are like young people's cells, and how they are different. Given the name of a "random damage theory" of cell aging, critique it. Describe the modern "theories" that focus on programmed self-destruction.

Given the name of a major body system, describe in reasonable detail the impact of aging on this system, and its significance (if known) to the individual.

Distinguish "age-dependent" and "age-related" diseases. Given the name of a disease of the elderly, tell whether it falls in either category.

Recognize the essential features of classic progeria and Werner's syndrome. Explain why neither syndrome is a perfect model for normal aging.

When a scientist asks, "What's happening as I get old?", be able to explain what we know, and what we don't know.

QUIZBANK

Aging (all)

INTRODUCTION

Shakespeare's Hamlet said that living too long is a "calamity".

In the coming years, you will learn a great deal about aging, both from your patients and your own experience. You'll be asked about "anti-aging therapies" (Hosp. Pract. 36: 43, 2001); the only stuff that clearly works remains extremely limited (hormone replacement, physical fitness). As more people live longer, the numbers and percentages of elderly people will increase. This also means more disabled people (Am. J. Pub. Health 81: 443, 1991).

It is almost impossible to predict who will and will not thrive during the later years (Am. J. Pub. Health 81: 63, 1991), though people can stack the odds in their favor (live longer, less disability at the end) by not smoking, by exercising, and by staying slender in middle age (NEJM 338: 1035, 1998). The implications of this to the health care provider are substantial.

Terms:

Primary aging / "senescence": The changes that we can expect as we get older, even if we remain healthy.

Secondary aging: The degenerative diseases and changes that become more common as we get older.

The actual basic biology of senescence (i.e., the post-maturational changes in the organism that cause loss of function) remains elusive (Proc. Nat. Acad. Sci. 88: 5360, 1991; West. J. Med. 153: 641, 1990; both nice reviews and still good). There are a few basic facts, however, that you can use in evaluating what you hear about "the causes of aging":

1. Each vertebrate species has a maximal life-span, at which an individual that has survived all of life's hazards will surely die. (For a human, this appears to be 115-120 years.) Inbred strains show only modest variations in maximal life-span (Genome 118: 693, 1988).

People who study these things calculate that if we found a cure for atherosclerosis and hypertension, we'd prolong the U.S. life expectancy by six years. A cure for all forms of cancer would prolong life expectancy by three years (Proc. Nat. Acad. Sci. 88: 5360, 1991).

2. As the limit of life span approaches, the body begins to show obvious signs of deterioration. Although long life and the attendant signs of "old age" are rare in the wild or in primitive societies, zoo animals and well-cared-for people who avoid disease and accidents still do not live longer than their longest-living wild counterparts.

3. The faster that individuals of a particular species mature, the shorter the maximal life-span of that species.

4. Cells from the higher animals will undergo only a limited number of cell divisions in tissue culture, unless they are cancerous or infected with certain viruses. For example, fibroblasts in culture will divide, at most, about 60 times; before that, after each generation, a smaller percentage of fibroblasts are willing to divide. This limited doubling capacity is the well-known Hayflick phenomenon ("finite doubling potential", "clonal senescence").

In other words, there is strong evidence that our bodies are programmed to wear out (provided, of course, that we don't die of disease or accidents in youth).

Sound paradoxical? Disturbing? Here's the best explanation I've found so far:

Most biologists agree today that sexual reproduction ("the way we re-shuffle genes, and allow individuals to accumulate advantageous mutations from several different ancestors") confers a strong Darwinian advantage on a species (for example, Nature 356: 706, 1992; Nature 373: 68, 1995; Science 278: 1562, 1997). Many contemporary theorists add that senescence ("removing the old to make way for the new") probably enhances this advantage (Nature 362: 305, 1993). If this is correct, old age and the certainty of death are the price we pay for the satisfactions of sexual love and parenthood.

* There is an elementary fallacy in the discussion of "the evolution of old age" in "Rubin and Farber". The author has confused selection for the long-term survival of individuals with selection for the long-term multiplication of their genes. The latter, of course, is what drives evolution.

Curiously, there is an autosomal recessive "Dorian Gray" condition of roundworms that significantly slows their growing-up and getting-old and delays their deaths (Science 249: 908, 1990; Nature 366: 404, 1993, gene coq7/clk-1, a ubiquinone synthesis gene -- how do you think that might work?) Several more mutations are now known. The best-known is an IGF-1 receptor (Science 277: 942, 1997); another is the regulator of the heat shock response (Science 300: 1142, 2003); The fact that these hasn't become the wild type helps confirm the above thinking (at least for me).

The methuselah gene in fruit flies confers longevity with increased resistance to heat, oxidants, and starvation. It's a G-protein-compled receptor somehow tied with heat shock proteins; the mechanism is still obscure (Nat Cell Biol 6: 540, 2004).

Closer to us, there are now at least seven genes in mice where certain mutations bestow longevity. Again, the fact that these have not become "wild-type" says something.

These include homozygous loss of growth hormone receptor, loss of p66(shc), or the fat-specific insulin receptor, or even heterozygous loss of the IGF-I receptor (Exp. Ger. 38: 1353, 2003).

The altered IGF-1 receptor signal is now emerging as a common pathway for longevity in worms, fruit flies, and mice, with several new long-life-promoting mutations recently discovered. Yet the known human mutations cause disease (Am. J. Med. 117: 882, 2004).

p66(sch) is central to a signalling system that tells cells subjected to oxidative stress to undergo apoptosis. In normal folks, stressed cells are more likely to die off in elderly individuals -- perhaps this will turn out to be a key mechanism (Science 305: 361 & 390, 2004).

CELLULAR AGING

Old cells (i.e., the cells of the elderly, regardless of when they last underwent mitosis) look the same as young cells, and the cells of the elderly do not look appreciably different from those of toddlers.

Of course, the older you get, the more lipofuscin you have in your heart muscle fibers, neurons, and liver cells (even babies have plenty in their hearts), but it seems doubtful that this sequestered pigment interferes with cell function.

However, old cells do not withstand a variety of challenges quite so well as younger cells. Supposedly they are more likely to undergo apoptosis when stressed, though how (and when or whether) this happens remains difficult to study (J. Ger. 56: B-475, 2001).

Further, in tissues in which cells normally undergo turnover, the rate decreases in the elderly. Today, much of this effect is attributed to methylation of cytosine bases near business genes (J. Lab. Clin. Med. 134: 333, 1999).

Ideas about why we age at cellular and molecular level may best be divided (departing slightly from "Big Robbins") into random damage "theories" ("wear and tear theories", "stochastic theories", etc.) and programmed self-destruction "theories". They are not mutually exclusive.

Random damage "theories" of aging focus on things that probably contribute both to early disease and death, and to some of the problems of old age. However, they probably can't explain the basics.

The free radical "theory" regards aging as due to the sum-total of free radical injuries.

This "theory" derives its "support" from the observation that radiation shortens the life-span of lab animals and humans. However, it appears to do this by causing diseases, and does not accelerate the signs of aging or decrease the life-span of animals that escape these diseases.

Despite much talk about "accumulated damage to DNA from free radicals", there seems to be no increase in amino acid substitutions in the proteins of the elderly. And although there is a massive literature on how mutations accumulate in mitochondria over a lifetime, similar evidence for nuclear DNA is conspicuous by its absence.

Further, while anti-oxidants increase the average lengths of life for some lab animals, they have utterly failed to prolong the maximum life expectancies for any species.

Mutants that produce large excesses of superoxide dismutase age just as rapidly as others. Fruit flies: Proc. Nat. Acad. Sci. 87: 4270, 1990. Mice: J. Ger. A 55: B5, 2000.

The antique claim that "life expectancy of a species is inversely proportional to its basal metabolic rate, because metabolism produces so many free radicals" is probably false-false (Proc. Nat. Acad. Sci. 78: 7124, 1981; Science 249: 902, 1990.)

The claim in "Big Robbins" that lifespan is inversely proportional to the amount of superoxide generated by mitochondria simply tells me that short-lived creatures can get away with producing more free radicals.

NOTE: The verdict is still pending on anti-oxidants to prolong the average human lifespan by forestalling degenerative disease. (* In the meantime, this is an easy "theory" to explain to the public, and unscrupulous "experts" still do this for big profits. Vitamin C and vitamin E probably don't even prolong life in animals: West. J. Med. 153: 641, 1990.)

The post-translational protein modification "theory" focuses on chemical changes in completed, functioning proteins that take place over long periods of time.

The best-known is non-enzymatic glycosylation of proteins (and perhaps even nucleic acids). This is the basis of the familiar "glycosylated hemoglobin" test for longstanding diabetic non-control. We know that non-enzymatic glycosylation of lens protein is probably responsible for certain kinds of cataracts, and "diabetics' vessels age faster than other people's".

Stay tuned on this one. Glycosylation of the vascular intimal matrix now seems to be chemotactic for monocytes, and also causes them to produced platelet-derived growth factor (Proc. Nat. Acad. Sci. 87: 9010, 1991). Could this be at the heart of the mystery of atherosclerosis?

* News: Aminoguanidine, which inhibits the formation of advanced glycation products, actually does slow the degenerative changes of aging in the renal vessels and heart (Proc. Nat. Acad. Sci. 93: 3907, 1996). This could be big news, and is the subject of considerable interest (Am. J. Kid. Dis. 35: 365, 2000, more).

4=Phenylbutyrate: So far, we're at the "fruit fly" stage. Proc. Nat. Acad. Sci. 99: 838, 2002.

Cross-linkages among connective-tissue molecules probably accounts for some of the stiffening of tendons and ligaments of the elderly. Tough to study -- but so far, this "theory" completely fails to explain most of the phenomena of aging.

The waste products "theory" attributes senescence to the "buildup of poisons" inside cells over many years. Some old-timers even blame lipofuscin. Perhaps some other toxic substance accumulates over the decades to finally poison us. If so, it has eluded our most diligent searchers. (* Of course, this "theory" is also popular with charlatans; ask 'em down at the enema parlor....)

The error-catastrophe "theory" cites hypothetical bad things that kill off individual cells, i.e., random errors of metabolism that generate, perhaps, a single very toxic molecule. This is a plausible (though currently unsupported) explanation for the gradual loss of brain cells over a lifetime. However, it can't explain the gradual decline of geriatric cells, or the immortalization of cancer or virally-infected cells.

The somatic mutations "theory" (most recently presented Mut. Res. 338: 25, 1995, and Mut. Res. 350: 35, 1996) claims that harmful mutations accumulate and account for cell failure. Overall, DNA repair mechanisms do work less well in the elderly (review: J. Gerontol. 44: 45, 1989), and mitochondrial DNA (Am. J. Resp. 154: 1141, 1996; J. Ger. 48: B-201, 1993; mt-DNA is not repaired very well) does seem to bear more mutations in the elderly; this finding is now robust, but it's not surprising -- there's little reason to repair DNA in mitochondria, since the bad ones will be selected out during early embryogenesis.

Ataxia-telangiectasia and Werner's are mutator phenotypes that resemble old age in some respects (see below) and contrast strikingly in others. However, we await a demonstration that chromosomal DNA is measurably more mutated in older people. And inbred animals (i.e., homozygotes for the right stuff at every locus, so burden-of-mutations should impact a cell less) do not outlive outbred animals (in fact, the reverse is usually true).

Programmed self-destruction "theories" are much more in keeping with the big picture of aging.

Obvious examples of programmed aging are found in nature. "Big Robbins" points out that Pacific salmon are programmed to age incredibly fast and die after spawning.

"Theories" of programmed aging begin with proposed explanations for the Hayflick finite doubling potential phenomenon, the wearing-out of laboratory cell-lines that have undergone mitosis many times.

You remember that the telomere is the repetitive sequence of (TTAGGG)n at the ends of the long DNA molecule that span each chromosome, and that these are elongated during gametogenesis.

It is now clear that much telomeric DNA is indeed lost from human cells over the course of many cell divisions, in vitro (Nature 345: 458, 1990; Am. J. Hum. Genet. 52: 661, 1993) and in vivo (Proc. Nat. Acad. Sci. 91: 9842, 1994); gametes have them re-spun. We do not know whether this loss is random or programmed.

Further, among rapidly-dividing cells, telomeres are shorter in the elderly than in the young (Nature 346: 866, 1990).

By now you have heard plenty about the famous DNA polymerase telomerase, which extends telomeres when cells divide (discovery Nature 337: 331, 1989).

*More on telomeres: NEJM 332: 955, 1995. Didja know that telomerase is a reverse transcriptase (PNAS 98: 8415, 1998)?

It seems reasonable to think that telomere loss evolved to protect us from cancers, especially cancers of stem cells that turn malignant after only a few hits. Older folks run out of stem cells. I trust that you can see why; this idea is starting to appear in print as well (J. Clin. Iniv. 113: 4 & 160, 2004).

We now know that in human fibroblasts, clonal senescence is due to loss of telomeres. When they get short enough, p53 recognizes that "the DNA has been damaged", and cell division ends (Science 291: 839, 2001).

In the 1990's, we discovered that introducing a senescent fibroblast nucleus into an immortalized cell often stops its division; introducing a young nucleus into a senescent fibroblast results in failure of either nucleus to enter S phase, etc. This fits nicely with the idea of p53 recognizing damaged telomeres.

* Rats and mice do not shorten their telomeres during cell division, and here's what's probably happening with them (and us). Fibroblasts grown under less-than-optimal conditions (i.e., cell culture) have a huge amount of p16^INK4a (Oncogene 15: 203, 1997; Nat. Med. 5: 731, 1999), which inhibits the cyclin dependent kinases that in turn phosphorylate the RB gene product (p110-Rb; Science 249: 666, 1990) so that cells can divide. More: Nature 396: 84, 1998. But under just-the-right cell culture conditions, mouse and rat cells don't Hayflick out (Science 291: 872, 2001).

You also recall that at least some viruses immortalize by inactivating p110-Rb; we have now immortalized smooth muscle cells using HPV E6/E7, which respectively tie up the p53 and Rb products (Proc. Nat.Acad. Sci. 89: 1224, 1992).

* Among age-matched older folks, the longer the telomeres, the longer the survival -- at least according to one group (Lancet 361: 393, 2003). If this holds up, it will have major implications.

Obviously, though, these explanations for failure of known mitotically-active cell lines cannot explain most of the problems of aging. It always seemed unlikely to me that the stem cells of the skin, bowel, and marrow double only fifty times; and now we know that mouse basal cells divide over 500 times in a mouse lifetime (Proc. Nat. Acad. Sci. 93: 1825, 1996). Even more seriously, in humans, it's the postmitotic cells (brain, mesenchyme, etc.) that bear the brunt of senescence.

* Only recently have we begun to identify genes that start making much more of, or much less of, their products as old age approaches (Arch. Derm. 130: 82, 1994). Some of the most interesting work in aging focuses on how these genes are turned on because of (????) mistakes during mitosis, which increase as we age (it seems to be programmed): Science 287: 2486, 2000. I invite you to read this study critically, since evidence of widespread genetic damage in the elderly remains conspicuous by its absence, and the cells seem to be involved rather uniformly rather than randomly as this idea would seem to predict.

The consensus nowadays is that no intervention slows aging in any experimental system, though such things as antioxidants, hormone replacement, and so forth can help avoid the degenerative changes and illnesses that shorten life (Mayo Clin. Proc. 75S: S3, 2000, big review).

Your lecturer predicts the following:

(1) Aging and senescence result from activation of genetic programs in key cells.

(2) The fundamental processes that cause aging are unrelated to mitotic activity or to the Hayflick phenomenon. The most important changes are programmed (i.e., catalyzed by regulator proteins coded by the genes themselves). Stochastic processes also play a minor role, but aging would proceed without them.

(3) These predictions will find massive experimental support during your lifetimes, and will surprise some people. Despite considerable excitement, delaying old age will prove even more difficult than curing disseminated chemotherapy-resistant cancer.

AGING OF ORGANS AND SYSTEMS

The immune system exhibits several changes in aging:

The ability of the body to make antibodies diminishes. Oddly, there are more lymphoid aggregates in the bone marrow and elsewhere.

"Big Robbins" claims there is an increase in autoimmune diseases among the elderly. I doubt this, but it is common to find a healthy older person with positive rheumatoid factor, anti-nuclear antibody, and/or false-positive syphilis screen.

The peripheral T-cells (helpers, suppressors; see J. Immunol. 144: 3569, 1990) proliferate much less exuberantly in old age. This is probably not due to the Hayflick phenomenon (as once claimed) since it's reported to be reversible in vitro (West. J. Med. 156: 641, 1991); T-cells from older people, independent of how many times they've divided, cannot make enough heat-shock protein (J. Ger. 49: B65, 1994), etc., etc.

Although most thymic tissue is gone by the late teens, it probably continues to replenish T-cell lines that are rendered non-functional by the Hayflick phenomenon or something else. The thymus becomes less able to do this with each decade (Genome 31, op. cit.).

Immunogerontology
Ed's update


Blood

Cell counts and parameters in old age are not significantly different from in young adult life. However, the cellularity of the bone marrow decreases moderately, and 30% cellularity on an iliac crest biopsy (which would be way-low for a young adult) is not unusual in an older person.

Endocrine glands

One of the most interesting recent findings in aging research is the discovery that some of the body-wasting and skin-thinning are due to diminished growth hormone production (NEJM 323: 1, 1990). Stay tuned; you may soon be using it clinically (J. Clin. End. Met. 84: 1288, 1999).

In women at menopause, the ovulation cycle becomes longer and eventually ceases. The problem is ovarian failure (no good follicles are left), and gonadotropins are extra high at this time (producing "hot flashes").

Men's Leydig cells are programmed to stop producing testosterone despite strong stimulation from gonadotropins. They can still divide, and for this reason, older men typically have more Leydig cells than younger men. There is also some gonadotropin failure. Old male rats have the same stuff: J. Ger. 49: B42, 1994. Nowadays, giving androgens to older guys who start feeling tired and depressed and start losing their libido is mainstream: Postgrad. Med. 115: 62, 2004. Some folks titrate depending on how the guy feels; others draw a serum testosterone first because the meds have some mild side effects (J. Clin. Endo. Metab. 89: 4789, 2004).

Glucose tolerance (i.e., the ability to maintain a low serum glucose after carbohydrate loading) diminishes slightly with advancing age, independent of all other considerations (Diabetes 40: 44, 1991). To treat or not to treat: Hosp. Pract. 26(4A): 29, April 30, 1991. The problem is insulin resistance from an unknown post-receptor defect.

Leptin is apparently not produced so efficiently by full fat cells in older folks (J. Clin. End. Metab. 83: 931, 1998.) This may be the key to weight gain as we age. Stay tuned.

Many of the elderly have low-ish TSH levels in the (alleged) absence of real hyperthyroidism (Arch. Int. Med. 151: 165, 1991).

Nervous system

Throughout life, neurons are lost from the brain (J. Ger. 47: B26, 1992). Although there is some slight memory loss in uncomplicated old age (correlating with hippocampal atrophy: Arch. Neuro. 50: 967, 1993), intelligence is basically preserved. As far as day-to-day living goes, the accumulated memories and life experiences more than makes up for the loss of neurons.

However, the most brilliant achievements in math and theoretical physics are generally made by people in their twenties.

Interestingly, one report suggests that the male brain seems to atrophy more on the left side, while the female brain atrophies more symmetrically. If confirmed, this could actually mean something; stay tuned (Proc. Nat. Acad. Sci. 88: 2845, 1991).

Histological changes typical of Alzheimer's disease (when numerous) make their appearance as people get older. It is still not clear whether this is part of "normal aging" or represents the appearance of Alzheimer's disease.

We are just starting to learn about changes in the neurotransmitters and other proteins of the brain as it ages. The changes are profound and include differential phosphorylation of important components that affect long-term function (Life Sci. 48: 373, 1991). Loss of dopaminergic neurons is currently much discussed; this may be part of the reason that psychoactive drugs are often effective in much lower dosages in the elderly.

Autonomic changes in the elderly are far more complex than simply loss of some sexual functioning.

Hearing loss among the elderly is common. Its impact: Lancet 337: 1181, 1991.

* If you believe "Big Robbins"'s claim that loss of brain cells in older people is "presumably" due to "atherosclerosis [narrowing] its blood supply", you'll believe anything. In fact, there's little correlation between atrophy and atherosclerosis, except when the latter is very severe.

Finally, the very-old typically, beginning at a particular time, stop eating or voluntarily doing other things to stay alive. ("Grandma! You've GOT to EAT!") "Anorexia of aging" is finally a recognized entity (Am. J. Clin. Nut. 66: 760, 1997). Even the JAMA (not noted as a bastion of non-interventionism) is now talking about letting these people go with dignity (273: 1032, 1995; "the old just die").

Heart and blood vessels

As the arteries grow hard, the heart grows soft.

-- H.L. Mencken

I thought no more was needed
Youth to prolong
Than dumbbell and foil
To keep the body young.

Oh, who could have foretold
That the heart grows old?

-- W.B. Yeats, 1918

Lipofuscin notwithstanding, there is no spectacular loss in the ability to the heart muscle to contract in advancing age.

Some myocytes die off, but the remaining ones compensate; there's also a bit of fibrosis (Am. J. Card. 76: 2D, 1995); the myosin type tends to change, making contraction slower and more energetically economical. This probably has a lot to do with loss of maximum cardiovascular potential as we get older.

Probably because of this, end-systolic and end-diastolic volumes do increase, and the left ventricle seems to relax and fill less readily (Am. Heart J. 121: 871, 1991). Perhaps this explains why relatively mild physiologic disturbances seem to cause older hearts to decompensate.

Definitely worth watching: The stiffness of old age (notably the cardiovascular system) seems to be reversible in animals upon administration of medicines that break up the glycation product cross-links (Proc. Nat. Acad. Sci. 97: 2809, 2000).

*Contrary to what you've been told, when the old person's heart starts to fail and to remodel, the myocytes primarily undergo hyperplasia rather than hypertrophy (J. Am. Coll. Card. 24: 140, 1994).

There is some fibrosis and myointimal cell proliferation in the arteries. The elastic in the arteries also breaks down, and the aorta becomes wider. This has nothing to do with atherosclerosis.

The valve leaflets may thicken a bit. The mitral valve annulus may calcify. Neither of these changes causes problems for most people.

"Atherosclerosis is a disease of the elderly", and (all other things being equal) bad-cholesterol rises with age.

Nitric oxide is produced less readily by vessels to keep themselves open.

As you might expect, male erectile-tissue smooth muscle loses much of its responsiveness to sympathetic-type chemicals (Br. J. Pharm. 101: 375, 1990).

Is it not strange that desire should so many years outlive performance?


-- Shakespeare, "Henry IV Part II"

Kidneys (Am. J. Kid. Dis. 16: 273, 1991)

The abilities to dispose of excess sodium or excess water, correct hyperkalemia, and concentrate urine are all diminished to some extent (Geriatrics 55: 26, 2000.

Individual glomeruli undergo fibrosis (* less often, "sclerosis", as in "Big Robbins"), and glomerular filtration rate diminishes in many (but not all) people. Old claims about a programmed linear loss of glomeruli have not held up.

Fibrosis of the intima of the small renal arteries seems to be closely related both to age and to blood pressure (Am. J. Path. 136: 429, 1990 -- I felt this intriguing study's correlations were "too good", but stay tuned).

*There is some thickening of the glomerular basement membrane, attributed to non-enzymatic glycosylation that crosslinks collagen (J. Ger. 49: M44, 1994).

Respiratory (Am. Rev. Resp. Dis. 143: 968, 1991)

There is some loss of elastic fibers in the lungs, leading to mild emphysema. This probably accounts for "senile hyperinflation"; unlike in smokers, there is little or no destruction of the alveoli (Chest 101: 793, 1992). We'll explain when we discuss emphysema.

*Don't forget sleep apnea as a cause of "dementia": Geriatrics 45(6): 16, 1990.

Muscles and bones

In old age, "sarcopenia" results, at least in part, from apoptosis of skeletal muscle fibers (J. Get. 58: 999, 2003). Long before, there is some diminution in the maximum athletic abilities of older people. However, a sixty-year-old who exercises regularly can expect to out-perform a teenaged couch-potato on most tests of sports fitness (see, for example, Am. Rev. Resp. Dis. 143: 968, 1991; Circulation 83: 96, 1991.)

Robert Redford Still fit at age 64

Sylvester Stallone Still huge at age 54

Chuck Norris Still fit at around 50

Charles Bronson Still fit over age 50

Harrison Ford Still fit at age 58

Clint Eastwood Still fit at age 70

An older person can't bulk his/her muscles as much as a younger person doing the same resistance exercises (J. Ger. 51: M-270, 1996).

*Though adequately perfused and oxygenated, the muscles of older mammals do not have the same maximum aerobic functional ability as do the young (Am. J. Physiol. 260: H-173, 1991). Perhaps the main reason for loss of maximum aerobic muscle capacity relates to substantially diminished mRNA synthesis by the mitochondria (Biochem. Biophys. Res. Comm. 176: 645, 1991).

Physicians are finally recognizing and talking about the severe muscle wasting that many older folks get. This causes much disability, and is now called "sarcopenia" (Mayo Clin. Proc. 75: S10, 2000).

I have never understood why physicians do not give anabolic steroids to the frail, muscle-wasted elderly. It is a big help for old rats. People began talking about it for humans in the 1990's (J. Ger. 49: B162, 1994), and now supplementing testosterone is mainstream, with none of the dire predictions about accelerated atherosclerosis or prostate cancer actually coming true (Am. J. Med. 110: 563, 2001).

Some degree of osteoporosis is found in all post-menopausal women and very old men. This is a function of physical inactivity, loss of sex hormones, etc., etc., as well as programmed bone loss.

Ligaments and tenons do stiffen from collagen cross-linkages.

Fibroblasts cultured from the elderly are less sensitive to a variety of growth factors (West. J. Med. 156: 641, 1991).

Curiously, "Big Robbins" does not mention osteoarthritis, one of the most important problems of the elderly. We will.

The ability of cartilage to regenerate its cells and matrix diminishes strikingly when the skeleton is mature: Arthr. Rheum. 38: 960, 1995. Clonal senescence is apparently the reason -- is this why older folks' get arthritis (Clin. Orth. 427-s: S-96, 2004).

Gut and liver (NEJM 322: 438, 1990)

Contrary to popular wisdom, neither the number of taste buds nor the sense of taste proper diminishes in the elderly. However, the sense of smell does decrease markedly.

Problems with swallowing are very common among the elderly, leading to both malnutrition and aspiration pneumonia.

Basal and maximal stomach acid production diminish sharply in old age. At the same time, the mucosa thins. Very little seems to happen to the small bowel (J. Clin. Path. 45: 450, 1992).

Mucosal diverticula in the large bowel are most common in the elderly. Many old people are constipated ("fewer than three bowel movements per week").

The liver looks normal, but hepatic blood flow may be lower than in a young person.

*Contrary to popular wisdom... at least in rodents, epithelial cell turnover in the gut actually increases in the elderly: J. Geront. 48: B43, 1993.

Skin stuff (Geriatrics 43: 49, 1988)

{25015} senile atrophy of the skin

The skin gets wrinkled, loses its elasticity and rete pegs, and both dermis and epidermis thin. Various spots (seborrheic keratoses, capillary hemangiomas, "senile" lentigos, others) appear. If these has been much sun exposure through life, solar elastosis becomes obvious.

Hair turns gray. In men, it often falls out over much of the head. (NOTE: Virtually all men lose the hair on their temples during their twenties. In "male pattern baldness", it continues to thin in the familiar distribution.) Hair may appear on a man's ears.

DISEASES OF AGING

According to "Big Robbins", certain diseases are inevitable if you live long enough. These are the age-dependent diseases. (Another definition might be "Diseases with prevalence increasing logarithmically with age.") A reasonable list (adapted from "Big Robbins") is:

• common (* "senile", * "age-related") cataract
• macular degeneration
• osteoporosis
• osteoarthritis
• vulvovaginal atrophy (women)
• nodular prostate hyperplasia (men)
• * Parkinsonism (very dubious)
• senile emphysema
• wrinkled skin
• presbyopia
• brain cell loss
• monoclonal gammopathy of uncertain significance
• senile cardiac amyloidosis, beta-pleased transthyretin ("prealbumin")

NOTE: In evaluating these claims, bear in mind that, beginning at age 20, the chances of dying during the next year from any cause increase exponentially for the duration of life (Proc. Nat. Acad. Sci. 88: 5360, 1991). This is Gompertz's law; the only suspected exception (?) at this time is the medfly (Science 258: 398, 1992).

And "Big Robbins" uses the term age-related for diseases that tend to show up first in older people. (Worth remembering: There is very little Darwinian selection against these diseases (* this idea is developed in Hosp. Pract. 32: 47, Feb. 15, 1997 though I am unable to follow some of the author's thinking.)

• atherosclerosis (stroke, heart attack, etc.)
• temporal arteritis
• myelodysplastic syndrome
• chronic lymphocytic leukemia
• plasma cell ("multiple") myeloma
• hypertension
• type II diabetes
• Alzheimer's disease (some would put it under "age-dependent" diseases; the controversy rages: JAMA 265: 310, 1991; "the curve levels off in the 80's" Lancet 346: 931, 1995)
• idiopathic Parkinson's disease
• prostate cancer
• skin cancer
• breast cancer
• colon cancer
• "atrophic gastritis" (stomach cancer precursor)
• calcific aortic stenosis
• Paget's disease of bone
• glaucoma
• iatrogenic disease and polypharmacy
• "vulnerability to infections"

If an age-related or age-dependent disease is not obviously inflammatory or neoplastic, it is called degenerative. This term is actually a confession of ignorance.

"SYNDROMES OF ACCELERATED AGING"

Certain diseases are alleged to represent "rapid aging". This is patently untrue; they are caricatures of aging. But at the least, they are interesting models for a number of degenerative diseases.

Classic progeria (* Hutchinson-Gilford syndrome) is a disease in which patients "appear to age too rapidly". This is now known to be a mutation in the lamin A gene (LMNA; * thanks once again, Dr. Collins), already the locus for six other known distinct syndromes (including an "atypical Werner's": Lancet 362: 40, 2003). The progeria mutation is supposedly almost always the same and always the result of a de-novo mutation in the sperm (Science 300: 1995, 2003). * Somehow the laminopathies cause diminished DNA repair, and perhaps this accounts for the increase in "degenerative disease" such as atherosclerosis in these children (Nat. Med. 11: 718, 2005).

Hutchinson-Gilford Progeria, ages 4 and 5

The epidermis is atrophic and lacks adnexal structures, the dermis is fibrotic (J. Derm. 26: 324, 1999), and there is accelerated atherosclerosis apparently due to a dramatic decline in HDL and adiponectin (J. Ped. 146: 336, 2005). Subcutaneous fat is lacking. The disease is obvious within the first two years of life, and death occurs in the teens from coronary artery atherosclerosis and myocardial infarction.

The current pop explanation that the altered lamin a makes the nuclear membrane is more physically fragile (hence the involvement of heart and vessels) doesn't make sense. These kids turn on some of the same genes as get overexpressed in normal older folks (Science 287: 2486, 2000), and their telomeres are shorter than others' (Am. J. Med. Genet. 103: 144, 2001).

{25627} progeria

Progeria Patient Photo

Progeria Patient Photo

Werner's syndrome, an autosomal recessive disease caused by a defective DNA helicase (WRN locus, Nat. Genet. 13: 11, 1996; Science 272: 258, 1996, update Am. J. Path. 162: 1559, 2003), features many mutations, especially deletions, and some of the stigmata of rapid aging (Proc. Nat. Acad. Sci. 86: 5893, 1989). The changes do not occur so soon in life as in "classic progeria", and patients generally function well until their forties. * Picture NEJM 337: 977, 1997.

Both diseases have several features that suggest "accelerated normal aging".

Patients fail to grow normally, even in youth. (Progeria babies are born tiny.)

The hair is lost early. The skin thins and develops local areas of hyperpigmentation. The nails become brittle and yellowed.

It's been claimed that widespread, premature loss of bone produces osteoporosis and fractures. (* In Hutchinson-Gilford, the bones are probably hypoplastic instead: Am. J. Med. Genet. 82: 242, 1999).

Gonadal function either doesn't develop or is lost prematurely.

Patients have high LDL levels and accelerated atherosclerosis. One component of (at least some cases of) Werner's syndrome is diminution in LDL receptors, much as in familial hypercholesterolemia (Eur. J. Clin. Invest. 20:137, 1990).

Werner's patients generally have loss of brain cells (sometimes with dementia), loss of glucose tolerance, premature graying of the hair and male pattern baldness, and cataracts (Arch. Gerontol. Geriatr. 9: 263, 1989).

Fibroblasts from Werner patients divide only about 20 times. Instead of loss of telomeres, the problem seems to be mediated by a "stress" gene (p38), which can be pharmacologically inhibited (J. Ger. 60: 1386, 2005).

However, there are many features of both diseases that dictate against a naïve acceptance of their representing "premature aging".

In classic progeria, the head is large, the jaw is small, the nose is beaked, and patients are bow-legged ("coxa valga", for future orthopedists). There is almost no subcutaneous fat. Instead of the kind of hair loss typical of old age, all the patient's hair follicles degenerate, leaving the body bald or covered with peach-fuzz. The "arthritis" from which these patients suffer is actually the accumulation of abnormal fibrous tissue surrounding the joints, and is totally unlike the classic arthritis syndromes of the elderly. Curiously, the distal ends of the clavicles are resorbed. The skin does not atrophy, and there is no dementia.

In Werner's syndrome, there are distinctive skin calcifications and hyperkeratinization, fibrosis of the sub-dermis (* "scleropoikiloderma"), and ankle ulcers, quite unlike anything in true "old age". Not surprisingly for a "mutations" syndrome, these patients have a strong tendency to develop certain cancers, but unlike the true elderly, these patients primarily develop sarcomas.

Neither group of patients develop the typical brain changes of "normal old age" (or, for that matter, of Alzheimer's disease).

Ataxia-telangiectasia, the "fragile chromosome syndrome", is shaping up as a third "progeria" (Nat. Genet. 13: 350, 1996).

These folks get gray hairs early, and get tumors faster, and get some other "degenerative" changes earlier.

One problem in ataxia-telangiectasia now seems to be exaggerated loss of telomeres with cell division, which leads to the great frequency of recombination observed in these patients.

* Definitely stay tuned. I'm almost ready to believe that gray hair represents loss of a melanin gene from loss of telomeres.

The gene ATM is presently credited with orchestrating the response to double-strand DNA breaks (Oncogene 21: 611, 2002). Much of the picture is still unclear.

Autosomal dyskeratosis congenita features a mutation in the telomerase complex, with inability of somatic cells to reconstitute their telomeres, and hence loss of epidermis and hematopoietic marrow. It also features "accelerated aging" (Lancet 361: 393, 2003; Nat. Genet. 36: 447, 2004; other loci are known, and work by a similar mechanism).

*There are a few other, even less convincing "progeria syndromes".

Leprechaunism, an insulin receptor mutation disease

Rothmund's syndrome is an autosomal recessive syndrome of mental retardation, skin pigment blotches, osteoporosis, cataracts, and increased cancer risk. It's yet another of the chromosomal instability syndromes; in some cases the DNA helicase RECQL4. A bunch more are listed in Am. J. Med. Genet. 35: 91, 1990; also Am. J. Med. Genet. 69: 169 & 182, 1997; Clin. Genet. 51: 200, 1997; most of these sound to this pathologist like connective tissue / skin problems.

Progeroid syndrome with early presentation but long life: Am. J. Med. Genet. 35: 383, 1990.

Another "progeroid syndrome" is an Ehlers-Danlos defect in galactosyl transferase I that produces "an aged appearance" to younger people (Proc. Nat. Acad. Sci. 87: 1342, 1990; I found nothing in this article to suggest "rapid aging").

The best match of a "progeria" syndrome in animals that mimics an increase in the degenerative diseases of aging is a mouse with defective mitochondrial DNA polymerase (Nature 429: 417, 2004). There are a host of other claims (including the hyped "klotho"); they are reviewed in Genetics 169: 265, 2005 with a discussion of how difficult it is to sort everything out.

"Xeroderma pigmentosum patients have accelerated aging of their skin and brain", etc. A new mouse without DNA repair "ages more rapidly" and gets more cancers: Mutat. Res. 383: 183, 1997.

Wiedemann-Rautenstrauch syndrome, or "neonatal progeroid syndrome" is autosomal-recessive, and usually lethal in the first year. It superficially resembles Hutchinson-Gilford's except that the only fat on the body is in the small of the back (Am. J. Med. Genet. 90: 131. 2000), and telomere lengths are normal (Am. J. Med. Genet. 103: 144, 2001). Cockayne syndrome, with defective repair of oxidative damage in nuclear DNA, features "accelerated aging" of the skin and accelerated graying of the hair, along with mental retardation, optic atrophy, and malformations. Gene Am. J. Hum. Genet. 62: 77, 1998. Cockayne forme fruste ("My skin ages faster than other people's"): J. Am. Ac. Derm. 39: 565, 1998.

*"The senescence-accelerated mouse" is our best model yet for some of the degenerative diseases of aging (amyloidosis, atherosclerosis, osteoporosis; Am. Rev. Resp. Dis. 150: 238, 1994, Atherosclerosis 118: 233, 1995; others). The exact genetic problem remains elusive; probably it's a genetic instability syndrome since there's an increase in somatic mutations. There are other strains of mice that get older faster; the differences between them and other mice are not spectacular. Stay tuned.

* Lab animals with enhanced p53 expression get less cancer but have shorter overall lifespans because of "accelerated aging" (Science 295: 28, 2002, more expected). Perhaps they are Hayflicking...

As DNA microassays are getting more and more sophisticated, people are starting to look at the expression profiles of many genes at once. After reading this handout, you won't be surprised to learn that cells from elderly humans, cells from humans with progeria, and human cells in cultures that have undergone clonal senescence exhibit three respective, totally different patterns of gene expression (Bioch. Biophys. Res. Com. 282: 934, 2001).

NOT THE LAST WORD ABOUT AGING:

Anything you can turn your hand to, do with whatever power you have; for there will be no work, nor reason, nor knowledge, nor wisdom in the grave where you are going.

-- Ecclesiastes 9:10

Ah, great it is / To believe the dream
As we stand in youth / By the starry stream;
But a greater thing / Is to fight life through
And say at the end, / The dream is true!

-- Fraternity lore; Edwin Markham

The National Academy of Sciences mandate for research in aging and training of geriatricians: NEJM 324: 1825, 1991 and Science 252: 1483, 1991. That's nice. One HMO generated a tremendous amount of paperwork "having a specialty team evaluate all its elderly people" without any apparent real-life benefit to the patients (NEJM 332: 1345, 1995). By contrast, when a hospital wing actually DOES some common-sense things to help the elderly get around during and after hospitalization, the benefit is striking (NEJM 332: 1338, 1995).

Nursing homes scandals have repeatedly showcased medicine-for-profit at its worst. The politicians' response has been to mandate that many tasks that any decent person could perform be relegated to high-paid people instead. Sorry, Uncle Sam; skill-and-caring isn't the same as educational-level. This cynical "solution", and the attendant bureaucracy, has led to ridiculous increases in the already-high costs of long-term care (JAMA 273: 1376, 1995).

One robust finding is that long-term severe calorie restriction in rats does prolong maximum lifespan, as well as average lifespan. Despite earlier claims of a spectacular increase, the newer studies show a prolongation of only about 10%, and these rats aren't exercising. By contrast, rats in the study that did a lot of aerobic exercise had prolonged average lifespans but the maximum lifespan was not increased (J. Appl. Physiol. 82: 399, 1997). Perhaps body cells undergo fewer divisions in the undernourished, as these rats' telomeres remain longer etc. (J. Geront. A 54: B502, 1999). Cells in these rats have less tendency to undergo apoptosis when stressed (as in the p66(shc)-knockout mouse): Science 305: 390, 2004. Works for roundworms too, though it offers no further benefit for the Dorian Gray strains (Proc. Nat. Acad. Sci. 95: 13091, 1998); current talk is that calorie restriction probably works by way of the IGF-1 receptor. Stay tuned. It's a provocative and well-substantiated claim -- but how productive do you think you'd be if you subsisted on only half of what a healthy person eats today?

Ask a health food store proprietor how, where, and at what age Old Man Rodale, the founder and guiding light of Prevention Magazine died. Also, his last remarks about his life expectancy....

"Aging" role-playing game: JAMA 262: 1507, 1989.

Elder abuse and neglect: NEJM 332: 437, 1995. Sometimes this is the revenge for which the child has waited a lifetime; sometimes not; regardless, you need to intercede to protect the old person, Doctor.

For a chilling tale about a group of "immortal" geriatric cases, read Jonathan Swift's account of the "Struldbrugs" in Gulliver's Travels, book III.

Shakespeare's King Lear (a must-read). Among the homeless mentally ill, the old king finally realizes that....

Andrew Marvell's To His Coy Mistress: Any English poetry anthology.

An aged man is but a paltry thing,
A tattered coat upon a stick, unless
Soul clap its hands and sing, and louder sing
For every tatter in its mortal dress.

-- W.B. Yeats "Sailing to Byzantium"

Shel Silverstein, The Giving Tree

Socrates's allegory of the cave: Plato's Republic.

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