Biochemical Insights into Progeria Syndrome Identify Bisphosphonates, Statins as Possible Candidate Drugs to Halt Aging

Can We Stay Forever Young?
May your heart always be joyful
And may your song always be sung
May you stay forever young
Forever Young —Bob Dylan

Beneath the rubric of orphan diseases reside some rare conditions and others that are extraordinarily uncommon. These are the diseases that most physicians either never to get to see or may have the opportunity to observe only a single case in their career. Within this group resides one disease so exceptionally rare that one of the largest published case series describing those afflicted with this singular disorder listed more co-authors (25) than it did patients (15).¹ It has been estimated that a mere 350 children worldwide suffer from this disorder, one so devastating because it mimics the aging process run amok. In fact, one movie, The Curious Case of Benjamin Button, starring Brad Pitt as a man who ages in reverse, touched on the emotional aspects of this illness.

Biology has advanced sufficiently to allow us to study the genomic details that shape an organism’s phenotype. Consider what happens when a single amino acid is switched from glycine GGC to glycine GGT in codon 608 of exon 11 in the lamin A (LMNA) gene. Instead of creating the code that produces lamin A, the fibrous protein responsible for providing structural function and transcriptional regulation in the cell nucleus, an aberrant protein, progerin, is manufactured instead.

Whereas lamin A is released by enzymatic cleavage and can harmlessly float away, progerin lacks this cleavage site and remains permanently anchored to the inner nuclear membrane, becoming an unwanted guest that wreaks molecular havoc with life-altering consequences. Progerin does everything wrong; it binds to the wrong proteins, it distorts the cell nucleus, it disrupts mitosis, and if this weren’t enough, it alters gene expression. The end result is the devastating Hutchinson–Gilford progeria syndrome, named after the two British practitioners who first described this illness in 1896 and 1897, respectively.

Progeria is one of 11 laminopathies caused by more than 180 known LMNA mutations that disturb or disrupt the nuclear envelope. Some are lethal, and others cause non-fatal, but serious, muscular and lipodystrophy syndromes. Cruel diseases all, but none so cruel as progeria, where a lifetime of aging is viciously compressed into a few decades of life. The affected child’s phenotype includes alopecia and sclerotic skin; bone growth abnormalities, including acro-osteolysis; hip, spine and clavicular anomalies; poor dentition; and a fatally accelerated aging of their heart and blood vessels, so that most affected children die from cardiovascular disease before they reach adolesence.¹

One of these children attended my kids’ elementary school, where his name is memorialized in the school library.²

Recent biochemical insights into progeria have identified some candidate drugs that may effectively metabolize progerin and displace it from the nuclear membrane. Interestingly, these include two widely prescribed agents used to halt certain effects of aging, bisphosphonates and statins.³ Although they appear to provide some benefit, they have not remedied the predicament of progeria.

This raises the question: Can aging be halted?

The solution to this vexing question would not only improve the lives of children with progeria, it would have the potential to dramatically alter society as a whole and profoundly disrupt the practice of medicine. Imagine a world where those diseases that rob us of our youth and grace disappear, where heart disease is rarely seen, where the hazards of osteoarthritis disappear and eliminate the need for joint arthroplasty, or where the incidence of neurodegenerative diseases declines precipitously, forcing nursing homes to shutter.

Skin Deep

Smetek / Science Source.com

We are nowhere near achieving these targets. In the interim, countless pills and minerals of questionable benefit crowd the anti-aging space. And of course there is one faux remedy for aging, a deadly poison turned dermatologists’ best friend—botulinum toxin A. This neurotoxin was best known as the highly lethal protein capable of paralyzing those ingesting it. Taming the botulinum toxin’s paralyzing effects led to it first being used in the neurology clinic, where its benefits in reducing muscle spasticity were readily apparent. Soon afterward, it migrated to the ophthalmologist’s chair, where it gained acceptance as a highly effective treatment for another spastic disorder, blepharospasm.

For years, it languished as a novel product for a niche market until the serendipitous discovery that when used to treat spastic eyelids, it also smoothed any nearby crow’s feet or under-eye wrinkles. For some of these patients, it seemed to turn back the clock. Quel visage! The toxin has acquired a growing list of clinical indications, ranging from migraine headache relief to managing overactive bladder function to relieving the spastic vascular supply in fingers afflicted by Raynaud’s phenomenon. Yet botulinum toxin’s greatest use remains cosmetic, magically creating a mirage—altering appearances.

If we are going to reverse the aging process, we need to better understand what is happening deep inside our cells. What actually causes us to age?

Vino Vivo

If we are going to reverse the aging process, we need to better understand what is happening deep inside our cells. What actually causes us to age? One of the most plausible explanations for the mechanistic basis of aging is the mitochondrial free radical theory of aging, which argues that aging and its related diseases are the consequence of free radical-induced damage to cellular macromolecules and the inability to counterbalance these changes by endogenous antioxidant defenses.⁴

Denham Harman, MD, the late emeritus professor of medicine at the University of Nebraska in Lincoln, originally proposed this theory in the mid-1950s. He suggested that free radicals produced during aerobic respiration have deleterious effects on cell components and connective tissues, causing cumulative damage over time that ultimately result in aging and death.⁵ Dr. Harman initially speculated that free radicals were most likely produced through reactions involving molecular oxygen catalyzed in the cells by the oxidative enzymes and enhanced by trace metals such as iron, cobalt and manganese. Approximately 90% of cellular oxygen is consumed within the mitochondria, mainly in the inner membrane, where oxidative phosphorylation occurs. According to the theory, oxidative stress attacks mitochondria, leading to increased oxidative damage. As a consequence, damaged mitochondria progressively become less efficient, losing their functional integrity and releasing more oxygen molecules, thus increasing oxidative damage to the mitochondria, and culminating in an accumulation of dysfunctional mitochondria with age. It’s as though the mitochondria have begun to rust.

One of the most intriguing compounds to emerge in the field of aging research has been resveratrol, a polyphenol found in grapes, red wine, chocolate and certain berries, which is considered to have antioxidant, anti-inflammatory and anti-cancer effects in humans.⁶ It has been considered to be responsible for the cardioprotective effects of red wine, better known as the “French paradox,” in which a low incidence of coronary heart disease occurs in the presence of a high dietary intake of cholesterol and saturated fat in France.⁷

The challenge we face is to age gracefully.
David Gifford / Science Source.com

Rheumatologists may be intrigued to learn that plasma concentrations of C-reactive protein and tumor necrosis factor (TNF) decline by about one-third in healthy subjects who ingested a plant extract containing resveratrol during a six-week study.⁶ In addition, peripheral blood mononuclear cell messenger RNA expression of interleukin-6 and TNF also decreased in this group.

How might resveratrol work on delaying aging? For the answer, we must refer to our baking and brewing friend, the lowly yeast cell, Saccharomyces cerevisiae, without which our stomachs would be full of flat bread and awful-tasting beer. Previous experiments in diverse organisms have shown that calorie restriction can slow the pace of aging and increase maximum lifespan. Some elegant studies using S. cerevisiae found that resveratrol mimics calorie restriction by stimulating certain selected protein enzymes known as sirtuins, which, when activated, increase the stability of the yeast’s DNA and extend its lifespan by 70%.⁸ Exciting news, yes. But does it work in humans?

One of the key investigators in the field created a company to commercialize the science of resveratrol that was purchased about 10 years ago by one of the large multinational pharmaceutical companies for over $700M.⁹ As is wont in scientific research, what looks to be a surefire hit often turns out to be a giant miss. Subsequent research hit a wall; resveratrol was an unstable compound to administer to subjects, its blood levels fluctuated greatly, and its effect varied widely with its concentration. Perhaps most critically for the new owners, resveratrol, being a natural compound, could not be patented as a drug. Five years after its purchase, the company folded.¹⁰

Better to Burn Out or to Rust?

Reversing aging will remain a vexing challenge for decades—if not centuries—to come. Drinking red wine is pleasurable, and perhaps doing so prolongs life. Some individuals have adopted a different approach. Take Google’s leading futurist, Ray Kurzweil, a fervent believer that dietary modifications “can help him live forever.”¹¹ He has predicted that humans will achieve this target by 2045, the year he turns 97. By his own admission, he spends upward of $1M per year ingesting about 100 various vitamins and supplements daily in an effort to enhance his health and delay the aging process. Good luck, Ray, and I hope Google’s stock price stays high!

For the rest of us, aging is a phenomenon that we have come to accept and, at times even embrace. Indeed, natural aging creates a pattern of predictability to our illnesses. For example, we don’t anticipate gout’s arrival before the fourth decade of life, nor should we expect to see the imprint of Drs. Charles Bouchard or William Heberden’s observations in the hands until some years later. Of course, it is uncanny how we can accurately predict when the alarm is set for developing polymyalgia rheumatica (PMR), a condition that is inextricably linked to one’s eligibility date for membership in the AARP and not a day sooner!

Let’s face it, life is a finite event. … Death is programmed inside every living organism, & this is a fact of life.

Let’s face it, life is a finite event. Despite Mr. Kurzweil’s unbridled optimism, this will likely remain the state of affairs for the next millennium and possibly beyond. Death is programmed inside every living organism, and this is a fact of life. This is simply Nature’s way of drawing the circle, linking life with death.

Unlike Mr. Kurzweil, some people hold a more pessimistic view of aging. Although I love his music, I question the Hobbesian choice offered by Neil Young’s lyrics: “It’s better to burn out than it is to rust.” The challenge is to discover the ways to age gracefully. A glass of Merlot, anyone?

Simon M. Helfgott, MD, is associate professor of medicine in the Division of Rheumatology, Immunology and Allergy at Harvard Medical School in Boston.

References

1. Merideth MA, Gordon LB, Clauss S, et al. Phenotype and course of Hutchinson–Gilford Progeria syndrome. N Engl J Med. 2008 Feb 7;358(6):592–604.
2. Kushner GS. When Bad Things Happen to Good People. New York: Random House (1987).
3. Varela I, Pereira S, Ugalde AP, et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med. 2008 Jul;14(7):767–772.
4. Gemma C, Vila J, Bachstetter A, et al. Riddle DR, ed. Oxidative stress and the aging brain: From theory to prevention. In Brain Aging: Models, Methods, and Mechanisms. Boca Raton, Fla.: CRC Press/Taylor & Francis (2007).
5. Harman D. The biologic clock: The mitochondria? J Am Geriatr Soc. 1972 Apr;20(4):145–147.
6. Semba RD, Ferrucci, L, Bartali B, et al. Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 2014 Jul;174(7):1077–1084.
7. Siemann EH, Creasy LL. Concentration of the phytoalexin resveratrol in wine. Am J Enol Vitic. 1992 Jan;43(1):49–52.
8. Howitz KT, Bitterman KJ, Cohen HY, et al Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6854):191–196.
9. Wade N. Doubt on anti-aging molecule as drug trial stops. The New York Times. 2011 Jan 10.
10. Timmerman L. GlaxoSmithKline shuts down Sirtris, five years after $720M buyout. Xconomy.com. 2013 Mar 12.
11. Brodwin E. Here’s the 700-calorie breakfast you should eat if you want to live forever, according to futurist Ray Kurzweil. Business Insider. 2016 Apr 20.

Correction

In the July 2016 issue, page 20 depicts an image of a plain film demonstrating an ankylosed LS spine, not a knee with osteoarthritis. We regret the error.