The Six Horsemen of Death: How They Stand Between You and Super Old Age

Believe it or not, Patient's Progress is not about the life cycle of the snowman. However, we did get another nine inches of snow yesterday and I was out building yet another snowman, my fourth of the winter. You should see him. He's the biggest, strongest and happiest yet and he is my newest and bestest friend.

No, this serial story is about living a long, healthy, and happy life and my snowmen, as much as I love them, are but fantastical little tastes of foolishness and joy along the way. Regularly doing childish, fun things like building a snowman kills those little stress goblins dead. And it may just be that with each snowman, I'll live a tad longer because of the snowman's gift of a smile and a chance to take a break from from old age.

Still, you can build snowmen until your back breaks and smile until your face hurts and it won't change the most shocking fact of life: death. There, in a story celebrating health and long life I have said the D word. I would much rather say “snowman.” A snowman is more fun than death.

Yet, one way or another, we must all come to terms with death. We must reach beyond the abstract death of the philosophical tome; the religious death of the church; the grieving death within families and among friends; the technological death of the hospital, the hushed-up death of the funeral parlor; the mass-denial death of society; and, especially, the oppressive death of fear and horror.

We must contemplate, understand, and embrace our own end. Death is natural, necessary, and a normal part of our cycle of life. Instead of keeping the poor despised and feared ghoul in the shadows, who, after all, only has a thankless job to do, we can bring him out into the open and get to know him better. There are many ways that this can be done, all of them human and life-affirming.

This is not to say that death is our friend. After all, it is the end of earthly life and for a living, breathing, moving creature, it is catastrophic finality. It may or may not be the end of consciousness, whatever that is. Consciousness is perhaps the greatest mystery of all. It certainly will take us away from earthly family, friends, love, large and little pleasures, and snowmen.

And, as much as we don't want to believe it or think about it, death is often painful, horrific, and tragic. In his fine book, “How We Die,” Sherwin Nuland, who has witnessed thousands of deaths as a physician, writes that the process is frequently drawn out, painful, ugly, and terrifying to the dying person.

Nuland, who prefers not to use “Dr.” as a writer, shows us that it is physically not easy to die. The body's immune system fiercely resists the process of death. When the first line of defense is breached, a second line is thrown into the battle.

When the second line fails, a third line rushes to the front, and then a fourth and a fifth, until the body has no troops left. Death frequently is a long, desperate fight to the last immunological soldier and for most of us the final struggle takes place in a hospital or nursing home.

According to Nuland, about 85% of people are finally overrun by what he calls the Six Horsemen of Death: atherosclerosis, hypertension, type II diabetes, obesity, dementia, and cancer. All weaken resistance to infection, opening the way for hordes of bacteria and all manner of microbes.

Nuland himself would like to avoid the Six Horsemen and die of old age. By that, he means having major organs wear out and shut down, ideally more or less simultaneously, and in one's sleep, and while one is still living fully. Feeling tired, one simply goes to bed and falls into life's deepest sleep.

Sounds good to me. At age 120 or so, having replaced all parts that can be replaced and with my brain mostly wasted away, I'll round up my last surviving brain neurons and vacate the premises shouting, “Come on in you gluttonous little carnivorous bastards and eat up because I'm – outta here!”

Unfortunately, both attaining this advanced age and having enough brain function left at age 120 to summon the microbian hordes are highly, highly unlikely, according to a tennis opponent this week who speaks with some authority. He is Donald Tipper, a longtime professor at Umass Memorial Medical School in Worcester and founder of its Department of Molecular Genetics and Microbiology.

He is currently researching vaccines against prion disease because he wants to and giving an annual lecture at the Medical School because he wants to. The Medical School gives him free lab space and he has a $50,000 grant from the National Institutes of Health. He has no specific teaching or work requirements.

I lift an eyebrow.

"They owe me," he says. He is 70 years old, lean, and athletic. Originally from England, he speaks with a pronounced British accent even after spending his adult life working in the U.S., more than 30 years at Umass Memorial.

As a tennis player, he can run off games with hard and deep groundstrokes from both sides. He hits the ball hard and well. He's competitive but does not need to win at all costs. "I just don't want to embarrass myself," he says.

Our match is hard fought and a terrific workout for us both. In singles, every ball is yours and you have to cover the whole court instead of half, as in doubles. For the record, I won but that was not the point for either one of us.We both had a great time and enjoyed ourselves. Of course, no matter how hard you want it not to be so, winning always feels better than losing.

After tennis, I went to see Tipper at Umass Memorial Hospital. His office and lab are in a secure area because scientists like Tipper work with potentially dangerous pathogens. So I must be escorted onto the floor and have the door locked behind me.

In his office, I mention that I have been reading about Alexander Fleming and exactly how he came to discover penicillin in 1928. "It was pure accident," I said. "He went out leaving a plateful of bacteria on the kitchen table. When he came back, mold had grown and created a bacteria-free zone on the plate. He saw that mold could kill bacteria."

"Yes, it was bad hygiene but good science," Tipper said. Then he brightens."You know, I was the one who proved his discovery."

"Really? I didn't know that."

That is not surprising because Tipper rarely talks about himself or his work. He is surprised that I am interested in what he is doing and quite willing to talk about his work. He is willing even after I tell him that "probably no one will ever read what I'm writing and that I'm only doing it because I want to."

"I understand perfectly," he said. "Yes, in 1965 I published a paper in The Proceedings of the National Academy of Sciences that indicated the mode of action of penicillin."

"How it works."

"Yes." He plucked what looked like a little metal work of art from his bookshelf and held it up. "This is penicillin. This is what it's molecular structure looks like."

After exactly 13 minutes, -- he had told me that he had to do something in 13 minutes -- we left his office and went down the hall and into a room where he retrieved a petri dish of bacteria from a wall-sized cooler set at 34 degress. "It has to be exactly 34 degrees," he said.

We went back to his lab where I watched him conduct an experiment, above, as part of his effort to find an effective vaccine against prion disease. Prions are infectious particles that cause fatal brain disease in animals and include scrapie, mad cow disease, and chronic wasting disease.

The infectious particles have the same amino acid composition as ordinary, natural proteins of the body. The prions turn deadly when they change shape or "misfold" and aggregate in toxic, killing clumps. These rogue prions invade brain tissues and force normal proteins to assume their shape and deadly work.

The result is dementia, loss of control of limbs, and death. The version of prion disease that affects humans usually occurs spontaneously and only rarely as a result of eating contaminated meat. There is no cure for prion disease.

But researchers like Tipper hope that by finding a vaccine against prion disease in animals, the way could be opened for its use in humans. A prion vaccine for humans is considered "theoretical."

Yet scientists must push forward. Tipper mixed and matched test-tubes of organisms and chemicals, introducing variables, trying to improve upon his "control" vaccine, the vaccine currently performing best when injected in infected mice. He is looking for the vaccine to elicit a strong immunological response.

He takes petri dishes of the current experiment and returns them to the big cooler at exactly 34 degrees. "Tomorrow we'll have a whole new batch of bacteria," he said.

This experiment would fail as does almost every experiment that he performs. That is the way of science: fail and keep failing until you succeed and then replicate. If Tipper eventually succeeds, he says there may be applicability to treatment for Alzheimers, a disease afflicting 4.5 million Americans.

When I ask him about longevity and what it takes to live to 120, he replies with a question: why would anybody want to? He says that I might be able to do it physically with a super-disciplined regimen of diet, exercise, health care and hitting the longevity lotto but I would most likely not have a functioning brain.

"You would be technically alive but you wouldn't be you," he said.

He gives me a little discourse on the brain and how the cells of our body function. Cells contain various proteins that perform different tasks ranging from garbage disposal to repairs of damage from misfolded proteins to communication.

The system works well, Tipper says, except for cells that have to live for a long time. These cells are the ones that show the growth of the misfolded protein that do the damage.

"The neurons in our brain have to last our entire lives. Unlike the cells of the gut, which turn over in a week, the brain cells we have at maturity do not reproduce themselves. They have to last 60 years and longer. What happens is that over time proteins in brain cells become more and more likely to misfold and accumulate in a form that the garbage system can't help.

"We lose .2% of our brain cells every year. In a 100 years, we lose 20% of our brain cells. We can do without 20% of our brain cells. But the accumulation of damage to brain cells accelerates the decline of brain function. This is the same mechanism that takes place in Alzheimers. Before that, you lose critical aspects of your personality.

"I don't want to live to be 120. My brain will wear out long before then. And Alzheimers is the way it is likely to wear out. We are not selected for longterm. What makes a person a person is what dies off even if the rest of the body is alive and functioning. My father-in-law is 90 and he is really sharp. I enjoy talking to him. How long he will stay that way I don't know. I only know that his brain is the same one he's had for 70 years and it will wear out."

So much for my living to age 120 and still being me. Nothing like a good reality sandwich to bring a dreamer down to earth. Tipper is telling me that exercise and diet and common sense can take me a long way, but not to continued personhood at age 120, not with this brain. In a few months, my grey matter will be 68 years old, which is already pushing it.

So I guess I have to get serious about finding a way to not get Alzheimer's.
Now I must reread that article by Sue Halpern in The New Yorker (Dec. 12, 2005) about research physicians at Columbia University's Taub Institute for Research on Alzheimer's Disease and the Aging Brain and their search to uncover the biological origins of the disease. The search is led by Richard Mayeux, a neurologist and epidemiologist.

Because almost half of early-onset Alzheimer's (between 30 and 60) is genetic and late-onset Alzheimer's (60 and over) is genetically-influenced, Mayeux's team is trying to find the risk-factor genes. There are thought to be about a half a dozen of them that increase one's risk of dementia.

The first risk-factor gene to be conclusively identified is amyloid precursor protein or APP. It was discovered in 1991 by geneticists at the University of London and is associated, in mutated forms, with early-onset Alzheimer's. The mutations cause overproduction of beta-amyloid and, without exception, people carrying the mutations develop Alzheimer's disease.

When APP was discovered, Malraux at first thought it was the Alzheimer's gene. But simple math told him it was not. Out of millions of cases of Alzheimer's disease, APP mutations were estimated to occur in fewer than two hundred. Within a few years, however, three more risk-factor genes were found and confirmed, two for early-onset and one for late-onset Alzheimer's disease.

However, despite the efforts of research teams all over the world, no one has found a new Alzheimer's gene in more than a decade. Hundreds have been claimed but none have been replicated by other researchers. Mayeux says it is like knowing that someone has committed a crime somewhere without knowing where and you have to look for the culprit all over the universe.

While they're looking, I guess I better find out if I have the one late-onset Alzheimer's gene that has been discovered. It is ApoE4 and is found in a quarter of the population and is a variant of a gene that we all carry. Many with the gene never get Alzheimer's. Many who do get Alzheimer's don't carry the gene.

Still, I and other geezers at least have a known perp to check out if we want to avoid one of Sherwin Nuland's Six Horsemen of Death – dementia. Unlike the the other five, dementia becomes almost inevitable as one gets to be 100 and 110 and 120 simply because we grow no new brain cells and the old ones get older and gradually die.

So I guess I better find out if I have the ApoE4 gene, lurking within me intent on killing my brain. Don't tell the ACLU, but I'm going to treat the suspect as guilty until proven innocent.

This is a matter of life or death, after all.

So long and keep moving.

 E-Books by George Pollock

 "State Kid: Hero of Literacy" is fiction based on his  real-life experiences  growing up in foster homes; "Last Laughs," is the true story of how five foster kids (he and four younger siblings) found their way in life and each other. "Killers: Surprises in a Maximum Security Prison," is the story of his being locked up for 23 hours with killers in a maximum security prison;  "I, Cadaver" is about his postmortem adventures and mischief in the anatomy lab at UMass Medical School. “A Beautiful Story” demonstrates the art and process of creative writing as a 16-year-old boy goes all out to write a story good enough to get him into an exclusive college -- on full scholarship; and "A Long, Happy, Healthy Life," which is about how to live the title every day.