Aging: Telomeres and Meatballs

Venture down the aisles of any drugstore and you will be bombarded with product labels promising to reverse the effects of old age—“age defying” creams to erase wrinkles and dark spots, vitamins and supplements for renewed energy, dyes to mask gray hair, and magic potions to regrow hair from oblivion.  If you have some extra funds at your disposal, you can indulge in some toxic facial injections (botox is short for botulinum toxin, which prevents nerve cells from communicating with muscles and is one of the most acutely lethal toxins known [1]) or rejuvenate sagging body parts with a bit of silicone.  But what causes the slowly encroaching physical signs that we are past our prime?  Scientists often gain understanding about a particular physiological process by studying cases in which that process goes awry.  Can the aging process go haywire?

“Wrapped in a voluminous white blanket, and partly crammed into one of the cribs, there sat an old man apparently about seventy years of age. His sparse hair was almost white, and from his chin dripped a long smoke-coloured beard, which waved absurdly back and forth, fanned by the breeze coming in at the window[…] There was no mistake—he was gazing at a man of threescore and ten—a baby of threescore and ten, a baby whose feet hung over the sides of the crib in which it was reposing.” [2].

Scott Fitzgerald’s short story The Curious Case of Benjamin Button tells the tale of a baby born an old man who then ages backwards throughout Screen Shot 2015-06-12 at 2.43.42 PMhis life and dies an infant. While there is no actual biological condition that entails aging backwards (or being born with full speech capacity and a crotchety disposition), the story was likely inspired by a rare disorder causing premature aging, known as Hutchinson-Gilford progeria syndrome (HGPS).  Children with HGPS have physical characteristics usually associated with old age—hair loss, hardened skin, prominent veins, and low bone density, to name a few.  The average life expectancy for a child with progeria is thirteen years, and the most common causes of death are heart attack and stroke [3].

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HGPS is caused by a mutation in a gene leading to faulty production of an important protein called Lamin A.  Normally, a precursor protein (named Prelamin A), is cut at specific spots to make Lamin A.  In HGPS, one of those incision points in the precursor is mutated, and the cellular scissors don’t know where to cut.  The cell cannot make lamin A.  Instead, the mutated, misshapen version of Prelamin A–called progerin–begins to accumulate. Buildup of progerin wreaks havoc, leading to a series of unfortunate events including misshapen cells, problems with cellular metabolism, and telomere aberrations. [reviewed in 4 and 5].  Let’s focus on telomeres.  Again and again science has pointed to a relationship between telomeres and aging.  To understand what telomeres do, first let’s talk about DNA.

DNA is like a book of recipes written in code.  Each cell in our body has a copy of this book and decodes the particular recipes needed for that cell type to function.  Each time a cell divides, it first copies the recipe book so that both daughter cells have a copy, just as a secret meatball recipe might be passed down through generations.  There’s a problem though—the printer is a little funky and sometimes when the book gets copied, the first page and the last page don’t make the new edition.  Luckily, our cells have telomeres—meaningless additions to each end of the DNA chromosomes like a bunch of blank pages at each end of the recipe book.  When telomeres get too short, the cell gets a signal that it must never divide again (a state called senescence)—because let’s face it, you might as well not pass the meatball recipe to your children if you can’t find a few pages of it.  We can’t have subpar meatballs.

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What does cellular senescence have to do with aging? With a few exceptions (such as most of our brain cells!) our cells do not live as long as we do—they die and are replaced by new cells.  We have pools of stem cells that copy their DNA recipe books and then divide, with one child cell becoming a new stem cell and the other becoming a specialized cell, for example, a new skin cell.  In HGPS, both lack of lamin A and the buildup of progerin cause premature telomere shortening [6, 7].  In those of us without the HGPS mutation, our stem cell telomeres are naturally shortened by years of division (which means years of page omissions by that glitch-prone printer), and can also be affected by carcinogens and UV damage. When the stem cell telomeres get too short and the stem cells stop dividing, they can’t help replace our body cells as they get old and tired.

In HGPS, this effect is seen especially in mesenchymal stem cells [5], which produce bone, skin, teeth, hair, fat, and blood vessels.  If these tissues are not well-maintained, bone density decreases, hair falls out, the heart becomes overworked.  Essentially, without our telomeres to preserve the recipe of life, we age.
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There is still plenty we do not know about aging, and scientists are still working to uncover the precise processes that occur in our cells as we age.  However, by studying cases such as HGPS–in which a single DNA mutation dramatically accelerates the aging process–we can learn a bit more about the important cellular mechanisms of aging.  Armed with new knowledge about aging–such as the importance of telomere length for the replenishment of our body cells from stem cells–we might be able to produce drugs that help protect our bodies from the physical effects of age.

While scientists toil away in labs to figure how to protect our telomeres and unlock the secrets to eternal youth, is there anything we can do at home?  A lot of anti-aging strategies you can probably already guess.  UV rays from the sun can damage DNA, so save your recipe books with vigilant sunblock application.  Try to eat healthy.  Not only is cholesterol putting stress on your aging blood vessel cells, but intermittent glucose spikes have been shown to induce cellular senescence (when a cell refuses to copy itself), and constant high glucose might actually shorten your telomeres [8].  (But, everything in moderation.  The antioxidants in dark chocolate can help protect DNA by lowering levels of little cellular menaces called reactive oxygen species).

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A recent long-term study done on a group of prostate cancer patients even suggests that good lifestyle habits might lengthen telomeres, not just slow shortening [9].  While telomere length decreased in the control group across five years, there was an average increase in telomere length in the lifestyle intervention group.  If you would like to implement their regime, it included four components: diet, exercise, stress management, and increased social support.  The prescribed diet was high in whole foods, plant-based protein, fruits, vegetables, unrefined grains, and legumes, and low in fat and refined carbohydrates.  Exercise was required often but at a low intensity: walking 30 min per day, 6 days per week.  De-stressing included yoga-based stretching, breathing, meditation, imagery, and progressive relaxation for an hour daily, and increased social support took the form of an hour-long support group session once per week.

So, treat your body well.  Take a minute to stop and smell the roses.  Make time in your busy schedules to engage with your friends.  You will be happier, and you just might help to preserve the waning number of blank pages protecting the sacred meatball recipe of life.

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References

  1.     Gill DM. Bacterial toxins: a table of lethal amounts. Microbiol Rev. 1982 Mar;46(1):86-94. Review. PubMed PMID: 6806598; PubMed Central PMCID: PMC373212.
  2.     Fitzgerald, F. S., & Brown, C. (2008). The curious case of Benjamin Button. New York: Collins Design
  3.     Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC,Zalewski C, Kim HJ, Solomon B, Brooks BP, Gerber LH, Turner ML, Domingo DL, Hart TC, Graf J, Reynolds JC, Gropman A, Yanovski JA, Gerhard-Herman M, Collins FS, Nabel EG, Cannon RO 3rd, Gahl WA, Introne WJ. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med. 2008 Feb 7;358(6):592-604.doi: 10.1056/NEJMoa0706898. PubMed PMID: 18256394; PubMed Central PMCID:PMC2940940.
  4.     Young SG, Jung HJ, Lee JM, Fong LG. Nuclear lamins and neurobiology. Mol Cell Biol. 2014 Aug;34(15):2776-85. doi: 10.1128/MCB.00486-14. Epub 2014 May 19. Review. PubMed PMID: 24842906; PubMed Central PMCID: PMC4135577.
  5.     Prokocimer M, Barkan R, Gruenbaum Y. Hutchinson-Gilford progeria syndrome through the lens of transcription. Aging Cell. 2013 Aug;12(4):533-43. doi:10.1111/acel.12070. Epub 2013 Apr 19. Review. PubMed PMID: 23496208.
  6.     Gonzalez-Suarez I, Redwood AB, Perkins SM, Vermolen B, Lichtensztejin D, Grotsky DA, Morgado-Palacin L, Gapud EJ, Sleckman BP, Sullivan T, Sage J, Stewart CL, Mai S, Gonzalo S. Novel roles for A-type lamins in telomere biology and the DNA damage response pathway. EMBO J. 2009 Aug 19;28(16):2414-27. doi:10.1038/emboj.2009.196. Epub 2009 Jul 23. PubMed PMID: 19629036; PubMed Central PMCID: PMC2735177.
  7.     Benson EK, Lee SW, Aaronson SA. Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J Cell Sci. 2010 Aug 1;123(Pt 15):2605-12.doi: 10.1242/jcs.067306. Epub 2010 Jul 6. PubMed PMID: 20605919; PubMed Central PMCID: PMC2908049.
  8.     Maeda M, Hayashi T, Mizuno N, Hattori Y, Kuzuya M. Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase. PLoS One. 2015 Apr 16;10(4):e0123169. doi: 10.1371/journal.pone.0123169. eCollection 2015. PubMed PMID: 25879533;PubMed Central PMCID: PMC4400006.
  9.     Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ, Magbanua MJ, Daubenmier J, Estay I, Hills NK, Chainani-Wu N, Carroll PR, Blackburn EH. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol. 2013 Oct;14(11):1112-20. doi: 10.1016/S1470-2045(13)70366-8. Epub 2013 Sep 17. PubMed PMID: 24051140.
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