Editor's note: This piece is the first of a two-part series. The second part will be posted in mid-November.
Old age in the 1600s, as famously described by William Shakespeare in As You Like It, presented a pretty miserable prospect:
"Last scene of all/That ends this strange eventful history/Is second childishness and mere oblivion/Sans teeth, sans eyes, sans taste, sans everything."
Shakespeare was in his mid-30s when he wrote that. Half of all those born along with him in England in 1564 had already died. Shakespeare himself barely made it past 50.
In the intervening 400 years, life expectancy in the United Kingdom — as in all developed countries — has more than doubled. A male child born in England or the United States today has a better than average chance of living well into his mid-70s, a girl into her 80s. Which means that around the world, there is a growing cohort of long-lived men and women playing out that final Shakespearean slow-death scene — 90-year-olds and 100-year-olds contending, with various degrees of success, against the cumulative "sans" of senescence. (Sans essence?)
It's that, the loss of vital spark, that's the old-age deal breaker for Ezekiel Emanuel, M.D., director of the Clinical Bioethics Department at the National Institutes of Health and a professor at the University of Pennsylvania. Overall, in his view, the quality of elderly lives hasn't improved much beyond Shakespeare's bleak assessment.
In a much discussed essay in The Atlantic last month, Emanuel declared that " … Living too long is also a loss. It renders many of us, if not disabled, then faltering and declining, a state that may not be worse than death, but is nonetheless deprived. It robs us of our creativity and ability to contribute to work, society, the world. It transforms how people experience us, relate to us and, most important, remember us. We are no longer remembered as vibrant and engaged but as feeble, ineffectual, even pathetic."
Given that wretched outlook, Emanuel titled his essay "Why I Hope to Die at 75." And he meant it, he insisted. Not that he'd kill himself if and when he reached that sell-by date, he explained, but he would at that point stop doing anything to prolong an increasingly diminished existence. No longer, for example, would he submit to regular preventive tests, screenings or surgical interventions. "I will only accept palliative — not curative — treatments if I am suffering pain or other disability," he wrote.
Well, We'll See
Emanuel, who is now 57, was prudent enough to "retain the right to change my mind." He could even, he admitted, imagine himself, should he remain hale and hardy, mounting an equally "vigorous and reasoned defense of living as long as possible."
And that could be a long, long time indeed. At least if biomedical gerontologist Aubrey de Grey is right. Perhaps even to the mind-boggling age of 1,000.
Yes. That third zero is no typo. De Grey is an English computer scientist turned biologist who earned a doctorate in the latter discipline from Cambridge, largely on the strength of a 1999 book, The Mitochondrial Free Radical Theory of Aging, in which he postulated a key mechanism underlying human senescence and suggested avenues to undoing it. He believes that a Methuselahic life span — a millennium — is not only within the realm of scientific possibility, but that even a person of Emanuel's age right this minute may be able to attain it.
De Grey is not just some crank. In addition to the requisite academic credentials, including an adjunct professorship at the Moscow Institute of Physics & Technology, he edits the journal Rejuvenation Research, and since 2009 has served as chief science officer for the nonprofit SENS Research Foundation in Mountain View, Calif. He founded the organization, which supports some 15 internal research programs as well as extramural projects at several universities, underwritten by a multimillion-pound allocation from his own inheritance.
SENS is an acronym that represents the obverse of all those Shakespearean sans. The letters stand for strategies for engineered negligible senescence — in simpler words, methodologies that will enable people to get older without getting sicker, weaker or barmier. Coined by de Grey, SENS is focused not on extending life per se, but rather on preventing and periodically repairing the various kinds of damage at and below the cellular level that produce the diseases and infirmities — from arthritis to cancer to cataracts to diabetes to heart disease to senile dementias to stroke — we now consider natural concomitants of old age.
Inflammation Is the Culprit
There are something like 100 trillion cells in the adult human body, and they're constantly wearing down under the stress of their work — secreting and absorbing proteins, jostling, bruising, splitting and otherwise figuratively living out their busy lives.
Cells are programmed to die after about 50 divisions. The suicide process is called apoptosis — but some exhausted cells, although no longer functional, refuse to bow out. They hang around to clog the works, hampering normal division by other cells and oozing toxic molecules that incite chronic inflammation. It's those inflammatory proteins — good guys when stirred up to fight acute infections by bacterial, viral or environmental pathogens, bad guys when ongoing conditions like allergies, gingivitis or cell senescence keep them simmering in the blood — that are "the primary contributor to every single major degenerative disease," stresses biochemist Judith Campisi, of Lawrence Berkeley National Laboratory and the Buck Institute for Research on Aging in Novato, Calif.
Cell senescence is one of the seven basic causes of the pathologies of old age, as categorized by de Grey. The others are:
- cell loss, when the rate of replacement lags behind the rate at which particular cells die — associated with weakening of the heart muscle, Parkinsonism and impaired immune response;
- accumulation of "junk" products outside the cell, like the amyloid plaque that clots the brains of Alzheimer patients;
- buildup of junk within the cells, as proteins are disassembled but normal enzymes are unable to digest all the remnants — implicated in atherosclerosis, heart disease, stroke and peripheral vascular disease, as well as neurodegenerative disorders;
- chromosomal mutations in cell nuclei that lead to cancer;
- mitochondrial mutations that impair normal cell functioning and underlie a host of morbidities — caused when free radicals generated during the mitochondrion's energy production attack its own DNA;
- excessive cross-linking between the proteins that bind cells together, causing tissues to lose elasticity — as in hardening of the arteries and farsightedness.
As scientists gain insight into these processes, they're devising more sophisticated interventions. That's the focus of activities fostered by the SENS Research Foundation, a sevenfold objective that includes:
- creating a drug that will induce apoptosis in senescent cells (Campisi's grail);
- restoring cells and tissues through stem cell therapies;
- stimulating the immune system to eliminate amyloid and other damaging extracellular junk;
- developing enzymes to help lysosomes break down more forms of junk molecules;
- seeking enzymes that will selectively sever harmful protein cross-links;
- copying mitochondrial DNA into the cell nucleus to shield it from the damaging free radicals produced within the mitochondrion;
- manipulating genes to deny cancer cells the telomeres they need to keep dividing endlessly.
The Eve of the Revolution?
For many years SENS and an allied, precursor organization, the Methusaleh Foundation, have sponsored biennial scientific conferences at Cambridge University, notes SENS CEO Mike Kope. In August, SENS convened its first Rejuvenation Biotechnology Conference in the United States. Some 350 leading academicians studying bioregenerative approaches to stemming aging, like Campisi, research directors from major pharmaceutical companies like Stephen Minger, chief cellular scientist at GE Healthcare in the United Kingdom, and Eric Siemers, M.D., head of the Alzheimer's disease team at Eli Lilly in Indianapolis, and private-sector entrepreneurs and venture capitalists gathered in Silicon Valley to learn the latest.
"It's obvious to me that university laboratories can't do it alone," says University of Southern California professor of gerontology and biological sciences Caleb Finch. "Big Pharma can't do it alone. A marketplace of ideas has to be developed. Those of us who come to these meetings have an increasingly broader set of professional alliances. You get a high table of very smart people around you who represent different disciplines and technologies."
"Disease-modifying cell therapy is very quickly becoming a reality," declares Minger. "We're all piling on this now. Until recently, pharma and biotech had no interest in the field — now everybody and his brother is setting up a cellular therapy program. There are a lot of Phase I and Phase II trials under way, with patients getting benefits. We're progressing very rapidly. A lot of money is being pumped in."
"Chronic diseases of aging account for the vast majority of health care expenditures," points out Campisi. "Traditionally, medicine has dealt with them by specializing. But people who study cancer, or neurodegenerative diseases like Alzheimer's, or painful osteoarthritis, or chronic obstructive pulmonary disease or congestive heart failure … they don't talk to each other. The evidence in medicine is growing, however, that old age is malleable. It may not be inevitable. There are underlying basic processes, and if we could intervene [at that level], no longer treat [separate diseases] but treat aging processes like cellular senescence, it would totally transform medicine."
Campisi has been experimenting with a recombinant drug that successfully flushes senescent cells from elderly transgenic mice — a far cry from proving efficacy in humans. And even the lifetime of these mutant lab mice is extended by only another 20 to 25 percent, she notes. (That might translate to 20 more years for a human.)
Finch is skeptical about how far a desirable human life can be stretched anyway. For one thing, half of those older than 85 today — three-quarters of those who've reached 100 — are suffering from dementia. The risk of dementia at every age is twice as great for people who're poor or have only a high school education. So, conquering Alzheimer's and its ilk will have to take priority, urges Finch — yet age-extending therapies are likely to be affordable, at least at first, only to the well-educated rich. (Lilly's Siemers believes "there's a 75 percent chance at least one of the disease-modifying Alzheimer's drugs now in Phase III trials" will prove effective.)
The kicker, Finch warns, is that global deterioration of the environment caused by climate change — especially pollution from the continued burning of fossil fuels — is piling an increasing inflammatory burden on our bodies. Will regenerative therapies be able to outpace the accumulating triggers to the inflammation response?
Next: Why Aubrey de Grey holds fast to his conviction that science today may let you — yes, you! — try to blow out 1,000 candles.
David Ollier Weber is a principal of The Kila Springs Group in Placerville, Calif., and a regular contributor to H&HN Daily.