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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. No texting or chat messages, please. Ordinary e-mails are welcome.
I am active in HealthTap, which provides free medical guidance from your cell phone. There is also a fee site at www.afraidtoask.com.
If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office. |
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.
I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:
pathology.org -- my cyberfriends, great for current news and browsing for the general public
EnjoyPath -- a great resource for everyone, from beginning medical students to pathologists with years of experience
Medmark Pathology -- massive listing of pathology sites
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures
Freely have you received, freely give. -- Matthew 10:8. My site receives an enormous amount of traffic, and I'm still handling dozens of requests for information weekly, all as a public service.
Pathology's modern founder, Rudolf Virchow M.D., left a legacy of realism and social conscience for the discipline. I am a mainstream Christian, a man of science, and a proponent of common sense and common kindness. I am an outspoken enemy of all the make-believe and bunk that interfere with peoples' health, reasonable freedom, and happiness. I talk and write straight, and without apology.
Throughout these notes, I am speaking only for myself, and not for any employer, organization, or associate.
Special thanks to my friend and colleague, Charles Wheeler M.D., pathologist and former Kansas City mayor. Thanks also to the real Patch Adams M.D., who wrote me encouragement when we were both beginning our unusual medical careers.
If you're a private individual who's enjoyed this site, and want to say, "Thank you, Ed!", then what I'd like best is a contribution to the Episcopalian home for abandoned, neglected, and abused kids in Nevada:
My home page
More of my notes
My medical students
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.
Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review. 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 do not accept donations, though I appreciate those who have offered to help.
During the eighteen 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 William Carey 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 William Carey for making it still 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!
We grow too soon old and too late smart.
-- Traditional
He who is ripe only in years is called "grown old in vain". He in whom dwell truth, virtue, non-violence, restraint, control -- he who is free from impurity and is wise, he is called an elder.
-- Dhammapada (attributed to Buddha)
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
You shall stand up before a grey-haired person, and honor the presence of an old person.
-- Leviticus 19: 32
Let your body go in the service of others.
-- Vivekananda
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
Grow old with me!
The best is yet to be,
The last of life, for which the first was made:
Our times are in His hand
Who said, "A whole I planned",
Youth shows but half; trust God:see all, nor be afraid.
-- Browning, "Rabbi ben Ezra"
May you live as long as you want to. May you want to as long as you live.
-- Traditional blessing
Oh to be seventy again!
-- Oliver Wendell Holmes, Jr., on the occasion of his passing a pretty girl on the street at the age of about eighty-five
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.
KCUMB Students
"Big Robbins" -- Cell Injury
Lectures follow Textbook
QUIZBANK
Aging (all)
INTRODUCTION Shakespeare's Hamlet reflected that it is a "calamity" to live too long. 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). Since the 1950's I've watched dozens of anti-aging schemes turn out to be expensive failures. Hormone replacement (as appropriate) and physical exercise help older folks far more than anything else we've discovered, but even these do not slow aging itself. 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. |
Van Gogh, On the Threshold of Eternity |
Terms:
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).
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.
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).
* Watch for the term "healthspan", the duration of good health, by analogy to "lifespan".
2. As the limit of life span approaches, the body begins to show obvious signs of deterioration.
3. The faster that individuals of a particular species mature, the shorter the maximal life-span of that species.
4. Cells from most of 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. We grow old and die as our final service to those around us.
* 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.
For the past two decades, we've been discovering autosomal recessive "Dorian Gray" mutations inf roundworms that significantly slow their growing-up and getting-old and delays their deaths (Science 249: 908, 1990; Nature 366: 404, 1993, gene coq7/clk-1, the first discovery, a ubiquinone synthesis gene -- how do you think that might work?) The best-known "Dorian Gray" locus today 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). Update and overviews J. Ger. A. 67: 511 & 587 & 599 & 611 & 626 & 640, 2012; Diabetes 61: 1315, 2012. |
* Not surprisingly, genome-wide searches for genes that are associated with healthy aging are being performed on people and mice; eight of the ten known loci are shared (J. Geront. 67: 470 & 495, 2012). Again, the fact that there has not been strong selection pressure for these to become wild-type invites the conclusion that they either diminish reproductive advantage, or that a shorter generation time is better for the species.
* The drug rapamycin / sirolimus inhibits the pathway in which IGF1r is central, and mice have their average (though from the data not their maximum) lifespans increased by its adminstration later in life (Nature 460: 392, 2009).
* The methuselah gene in fruit flies when mutated (downregulated) confers longevity with increased resistance to heat, oxidants, and starvation, at the price of diminished fertility. It's a G-protein-compled receptor somehow tied with heat shock proteins; the mechanism is still obscure (Nat Cell Biol 6: 540, 2004; Nat. Chem. Bio. 3: 415, 2007).
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" favors the idea that it's to your genes' advantage to have you replaced in a timely way.
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). See below.
Mutations that confer longevity are starting to be detected. Some p53 mutations are well-established longevity genes in roundworms (Science 313: 971, 2006), mice, and in one study in Danish adults (J. Exp. Med. 204: 1295, 2007).
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.
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 (and their tendency to overgrow individual cells: Lancet 360: 1323, 2002), similar evidence for nuclear DNA remains 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 some textbooks 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.
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".
* Aminoguanidine ("Pimagedine"), which inhibits the formation of advanced glycation products, was a disappointment as far as saving kidneys or prolonging life. You can now get it at the health food store.
* 4-Phenylbutyrate ("phenibut"): Helped fruit flies, but just makes people tired. Proc. Nat. Acad. Sci. 99: 838, 2002.
* ALT-711 (alagebrium; Am. J. Hypert. 17: 23-S, 2004; J. Hypert. 25: 577, 2007, more) proved yet another major disappointment.
CROSS-LINKAGES AMONG CONNECTIVE-TISSUE MOLECULES (by glycosylation products and so forth -- Exp. Diab. Res. 5: 143, 2004 and others) 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" (classically 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 (Am. J. Path. 172: 1445, 2008), 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.
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).
For that matter -- do you believe that exercise in humans up-regulates telomerase in WBC's? Studies on both rats (WBC's, endothelium) and track-and-field athletes ("peripheral blood leukocytes") suggest "Yes" (Circulation 120: 2438, 2009). Stay tuned.
And, by the way.... the telomerase knockout mouse (mTERC(-/-) (Cell 91: 23, 1997; Carcinogenesis 31: 9, 2010) is a remarkably healthy creature.
* Preliminary findings: The shorter the telomeres, controlling for everything else, the greater cancer risk, especially the nastier cancers -- perhaps some people simply divide their cells more often. Stay tuned: JAMA 304: 69, 2010).
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. Maybe older folks do 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).
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 p16INK4a (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.
Be this as it may, today, we use telomere shortening (easily assayed by in-situ fluorescence) and staining for the proteins p16INK4a and p21WAF1/Cip1 as measures of "cellular senescence" (for example Am. J. Resp. Crit. Care Med. 174: 886, 2006).
* "Some people age faster than others" --and maybe this correlates with telomere length in the circulating blood. The idea has been around for ten years and is fairly robust (BMJ 344: e1727, 2012 -- but what would you do with this information clinically?
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. |
* In the 1990's, we began 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 predicted the following in 1985. So far, they seem to be supported by
the data.
(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.
Allergies tend to get much less severe.
"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.); one mouse study suggests that slowing aging by caloric restriction also slows this (J. Immuno. 183: 3040, 2009).
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.
* Even among animal experimenters, there remains no impressive data on changes in marrow elements. The most impressive so far is a tendency, in older mice, to lose stem cells committed to differentiating to lymphocytes (Blood 111: 5553, 2008) -- but this makes sense, as there'd be no reason to continue producing there.
Macrophage precursor telomeres do shorten, supposedly limiting their ability to respond to some colony stimulating factors but not others; they also withstand oxidative stress less well, a trait also seen in telomerase knockout mice (Terc(-/-)): J. Immuno. 183: 2356, 2009).
ENDOCRINE GLANDS
One of the most interesting findings in aging research during the 1990's was the discovery that some of the body-wasting and skin-thinning are due to diminished growth hormone production (NEJM 323: 1, 1990). This is now well established (older review J. Clin. End. Met. 84: 1288, 1999; newer work Hormones 7: 133, 2008) and is called "somatopause". Whether and who gets supplemented will be worked out in the coming years.
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). Nobody really understands it (Urol. Clin. N.A. 39: 63, 2012).
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. The ability of beta cells to regenerate drops markedly: J. Clin. Inv. 123: 990, 2013.
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 -- still valid Arch. Neuro. 66: 1385, 2009), 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.
In the absence of Alzheimer's, brain cortical atrophy (i.e., loss of gray matter volume) involves the primary sensorimotor and nearby association areas, and the middle cingulate gyrus, thalamus, and cerebellar cortex. Alzheimer's tends to involve the parahippocampus, and precuneus. Both do tend to involve the hippocampus (Neurology 73: 1899, 2009).
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 -- the UK brain bankers found cortical atrophy, but not "Alzheimer histology", to correlate well with dementia in older folks (NEJM 360: 2302, 2009), while young folks with Alzheimer histology were usually demented. In the absence of dementia, there's often plenty of amyloid and hippocampal atrophy; they tend to run together (Neurology 74: 121, 2010).
The increasing size of the cerebral ventricles is the parameter that correlates best with the increase in Alzheimer and vascular pathology in the brain: JAMA Neuro 70: 616, 2013.
HIPPOCAMPAL SCLEROSIS OF OLD AGE is the name that's now given to a common change in the old-old (10% of 85-year-olds, increasing steadily afterwards). It's an autopsy diagnosis, not possible to distinguish from Alzheimer's and some other entities on scan. There is marked loss of neurons and replacement by glia in each hippocampus, unassociated with Alzheimer pathology. There's an immunostain that distinguishes it from the hippocampal sclerosis (often unilateral) that's common in temporal lobe epilepsy and can best spotted on scans (Brain 134: 1506, 2011). age-related, with
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. It is commonly missed (JAMA 307: 1185, 2012).
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 (Anesth. Analg. 112: 1408, 2011)
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
-- W.B. Yeats, 1918
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Lipofuscin notwithstanding, there is no spectacular loss in the ability to the heart muscle to contract in advancing age in the absence of the deformation of the left ventricle characteristic of "congestive heart failure of the elderly."
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 less easily and fill less readily (Am. Heart J. 121: 871, 1991; update on the diastolic dysfunction of aging JAMA 306: 856, 2011). Perhaps this explains why relatively mild physiologic disturbances seem to cause older hearts to decompensate.
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). This may be an age-induced change.
No one really knows how much this happens in humans, but there's a rat model of "age-related cardiac dysfunction" in which increased apoptosis of cardiac myocytes leads to the pathological remodeling of the heart also seen in old folks' CHF (J. Geront. A. 65: 147, 2010).
* And for what it's worth, the stem cells in the heart that seem committed to replacing the heart muscle fibers have lost their telomeres and are non-functional (Am. J. Path. 179: 349, 2011).
There is some fibrosis and myointimal cell proliferation in the arteries. The elastic in the arteries also breaks down, and the aorta becomes wider. Don't confuse these changes with atherosclerosis in the large argeries. The smaller arteries have some loss of smooth muscle and its function, which currently is blamed on lifelong exposure to angiotensin II (molecular biology, p53 and apoptosis Circulation 114: 953, 2006).
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 -- this has stood up, and probably nephrosclerosis is inevitable as we age: Ann. Int. Med. 152: 561, 2010).
* There is some thickening of the glomerular basement membrane, attributed to non-enzymatic glycosylation that crosslinks collagen (J. Ger. 49: M44, 1994).
RESPIRATORY (J. Ger. A. 67: 364, 2012)
There is some loss of elastic fibers in the lungs, leading to mild emphysema. (The FEV1 drops by several mL every year during your adult life: Am. J. Med. 119(10 S 1): 4, 2006. The loss of elasticity 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.) You'll learn formulas to detect sarcopenia (basically, loss of skeletal muscle) even in the presence of obesity (J. Ger. 68: 168, 2013 -- from Framingham, older folks who have trouble getting around tend to be sarcopenic; related study J. Ger. 68: 80, 2013 found that losing fat through diet helps even sarcopenic folks get around.)
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). However, an older man who does hard physical work can almost certainly beat today's typical videogame-playing teen at any test of strength.
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). An old idea that could well be true is that the loss of maximum aerobic muscle capacity relates to substantially diminished mRNA synthesis by the mitochondria (Biochem. Biophys. Res. Comm. 176: 645, 1991). The fact that the mitochondria in older folks' muscles just don't work as well is now a robust finding (J. Ger. 63: 350, 2008). Various mechanisms are proposed -- the whole business remains arcane and since the muscle cytosol seems to mediate much of the dysfunction, it can't be the result of "accumulated mutations" (J. Geront. A. 65: 138, 2010). The McMasters' crew finally got enough "senior athletes" to match a group of equally-active younger folks and, yes, older folks do have fewer mitochondria in skeletal muscle, and more apparently-useless lipid vacuoles lying around (J. Ger. A. 65: 119, 2010).
Be this as it may, a team at Pittsburgh recently found that if older folks exercise, the numbers of mitochondria in their muscles increase impressively (about half-again-more) over their couch-potato peers, and they also transport electrons better (J. Ger. 61: 534, 2006). "The role of mitochondria in aging": J. Clin. Inv. 123: 951, 2013.
The new imaging techniques have shown that older men have more fatty ingrowth (i.e., fat cells) in the muscle (J. Geront. A 65: 295, 2010). If there's a link to metabolic syndrome markers, it's not striking.
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).
* Less deadly -- the weakening of the tissues around the mouth produces the "frowning" change of old age. How plastic surgeons repair it: Plast. Recon. Surg. 125: 667, 2010.
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).
* The glycogen synthetase kinase-3 (GSK-3) knockout mouse as a model for accelrated aging of skeletal and cardiac muscle: J. Clin. Inv. 123: 1821, 2013.
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 tendons 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). Wound healing and tissue repair are somewhat diminished in older people, but it's hard to measure and there's still more speculation than hard fact (Clin. Pharm. Therap. 91: 21, 2012).
Curiously, "Big Robbins" hasn't always mentioned 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)? Clonal senescence in arthrtis degeneration is now a robust finding, with some of the bad things such as oxidized-LDL making it worse by suppressing telomerase activity (Arth. Rheum. 60: 3007, 2009).
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).
The muscle wasting seen in skinny older folks probably has at least as much to do with diminished food intake as with loss of hormones. We're already mentioned "anorexia of old age" and while nobody understands it any more than we understand "somatopause", there's talk about ghrelin not being produced adequately in old age (Endocr. 149: 3722, 2008).
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.
Hepatocytes probably have unlimited regenerative potential, but the bile ducts (which are seldom damaged except in chronic liver disease) do not (Am. J. Clin. Path. 133: 212, 2010). It's worst in primary biliary cirrhosis, but probably important as well in NASH and hepatitis C. As NASH in particular becomes a major killer, look for a cholestatic form in the elderly.
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: All normal men lose the hair on their temples around age 20. 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:
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 one suspected exception (?) that I know is the medfly (Science 258: 398, 1992; update on the incomprehensible longevity of some medflies Aging Cell 7: 426, 2008).
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.)
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".
The illness is so rare that it took the NIH until 2008 to publish a series of 15 patients, further characterizing the syndrome (NEJM 358: 592, 2008).
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There is a specific loss of smooth muscle cells from the media of the blood vessels; these are replaced by collagen and matrix. This is duplicated in the mouse model Proc. Nat. Acad. Sci. 103: 3250, 2006).
There is also 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 at age 12-13 from coronary artery atherosclerosis or stroke.
* The first 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, since one would expect the nuclei of the beating heart to be annihilated before birth. I called this in 2003; it's now clear that the nuclei are not more fragile mechanically (Proc. Nat. Acad. Sci. 103: 10271, 2006).
Newer work looks at increased apoptosis, especially of the body's reserve cells (J. Geront. Series A: 62: 3, 2007).
As major structural proteins of nuclei, the lamins also do affect what genes are expressed. 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). Attempts to link sporadic changes in lamin A in older adults without progeria are in their infancy; for one thing, it now seems that there are plenty of liver cells in "normal" older folks that contain progerin instead of lamin A (Science 312: 1059, 2006).
* Other progeroid syndromes at the LMNA locus: J. Clin. Endo. Metab. 94: 4971, 2009.
{25627} progeria
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.
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).
Telomeres are shortened in Werner syndrome cell cultures, at least in the mouse model (Nat. Genet. 36: 877, 2004). The cells undergo clonal senescence early, after around 20 divisions. * Picture NEJM 337: 977, 1997.
Both diseases have several features that suggest "accelerated normal aging".
Patients fail to grow normally, even before birth. (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.
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. In 2001, I predicted that the biology of graying of the hiar was due to loss of a gene as telomeres shortened. Support for this idea -- Chest 140: 753, 2011. Stay tuned.
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.
* There are a few other, even less convincing "progeria syndromes".
LEPRECHAUNISM, an insulin receptor mutation disease
ROTHMUND'S SYNDROME (Rothmund-Thomson) 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").
Mandibuloacral dysplasia is an autosomal recessive disorder with mutated lamin A/C or zinc metalloproteinase; there is probably another locus (J. Clin. Endo. Metab. 95: E192, 2010).
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 mouse without DNA repair "ages more rapidly" and gets more cancers: Mutat. Res. 383: 183, 1997.
WIEDEMANN-RAUTENSTRAUCH, 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; many others). There are several strains, but the genetics remains elusive. The SAM-P8 strain gets metabolic syndrome X (J. Geront. 62: 1219, 2007). There used to be talk of increased rates of somatic mutations (Nat. Genet. 19: 116, 1998) but this idea has not held up. Today the emphasis is on overproduction of reactive oxygen species by defective mitochondria (strain SAM-P11; J. Geront. 60: 1087, 2005). 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; Mech. Ageing 124: 599, 2003; 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).
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.
Ah, great it is / To believe the dream
-- Ecclesiastes 9:10
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 whatsoever 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?
* Speaking of roundworms, initial reports are that the anticonvulsants ethosuximide, trimethadione, and one that people don't use slow aging and prolong lifespan in roundworms (Arch. Neur. 63: 491, 2006). Just a pilot study; the neurodegenerative changes of older roundworms seemed to be what was delayed.
* 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; Arch. Path. Lab. Med. 130: 1290, 2006 ("differential diagnosis"). Sometimes this is the revenge for which the child has waited a lifetime; sometimes not; regardless, you need to intervene 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.
The historic Cyrano de Bergerac wrote an early science-fiction piece about a voyage to the moon (published 1657). When a Lunar citizen feels the mind and body wearing out, the community holds a party and the citizen reviews his or her life. If the peers decide the life was a good one, they kill the person. If not, the punishment is old age.
Shakespeare's King Lear (a must-read). Among the homeless mentally ill, the old king finally realizes that.... |
His jester and King Lear |
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. |
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about this topic in pathology to consult these standard textbooks.
In my notes, the most helpful current journal references are embedded in the text. Students using these during lecture strongly prefer this. And because the site is constantly being updated, numbered endnotes would be unmanageable. What's available online, and for whom, is always changing. Most public libraries will be happy to help you get an article that you need. Good luck on your own searches, and again, if there is any way in which I can help you, please contact me at scalpel_blade@yahoo.com. No texting or chat messages, please. Ordinary e-mails are welcome. Health and friendship!
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