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Becoming pro-geriatric by understanding progeria

DII small banner By Warren R. Heymann, MD
Aug. 13, 2018

A fifteen-year-old boy with Hutchinson-Gilford progeria syndrome.
Credit: JAAD

I have never seen a case of Hutchinson-Gilford progeria syndrome (HGPS). You probably haven’t either, given its incidence of 1 in 4 million. Why comment on a disease that will likely only be seen in a textbook? Aside from the immediate importance to afflicted patients and their families, new advances in treating HGPS offer a window into the future of anti-aging that should pique our interest.

HGPS is an autosomal dominant disorder characterized by a normal appearance at birth, but presenting in infancy with failure to thrive, an aged appearance, alopecia, progressive lipoatrophy, joint contractures, skeletal dysplasia, and atherosclerosis which usually leads to their demise (by myocardial infarction or stroke) at an average age of 14.6 years. Intellectual development is normal. (1)

If you have never met anyone with HGPS, I recommend that you watch the fabulous Ted Talk given by the indomitable Sam Berns [1996-2014] who discusses his philosophy for a happy life.

The nuclear lamina (NL) is present in all animals and is composed of type V intermediate filaments called lamins plus lamin associated proteins. Mammalian genomes contain 3 lamin genes: LMNA, which encodes lamin A and lamin C (A-type lamins), as well as LMNB1 and LMNB2 that encode lamin B1 and B2 (B-type lamins), respectively. The lamin A precursor also contains a CaaX motif and is initially farnesylated. Proteolytic cleavage by the ZMPSTE24 protease removes the last 15 amino acid residues and the hydrophobic farnesyl group to produce mature lamin A, which is found both at the NL and in the nuclear interior. (2)

HGPS is one of the laminopathies, caused by a (usually sporadic) mutation in the LMNA gene. The mutation activates an alternative splice site, resulting in accumulation of an abnormal lamin A-derived protein named progerin. Progerin lacks this crucial cleavage site, resulting in a permanently farnesylated protein that accumulates in, and causing thickening of, the nuclear membrane. (1) Progerin-associated cellular defects include nuclear blebbing and stiffness, (epi)genomic derangement, transcriptional dysregulation, mitochondrial dysfunction, disrupted protein homeostasis, accelerated senescence, and cell death. (3)

Four potential treatment strategies for HGPS have been elaborated: 1) Use of prelamin A isoprenylation and methylation inhibitors such as lonafarnib [isoprenylation or lipidation is the addition of hydrophobic molecules to a protein; farnesylation is a type of isoprenylation]; 2) Autophagy-activating drugs including rapamycin and everolimus; 3) Downregulation of prelamin A aberrant splicing with antisense nucleotides or metformin; and 4) Reduction of progerin downstream toxic effects, an example being N-acetyl cysteine acting as a reactive oxygen species scavenger. (4)

In a cohort study of 27 HGPS patients treated with the farnesyltransferase inhibitor lonafarnib, compared with a pool of 103 contemporaneous untreated patients, treatment with lonafarnib monotherapy was associated with a significantly lower mortality rate (3.7% versus 33.3%) after a median 2.2 years of follow-up. The benefit was cardiovascular and neurologic — the dermatologic manifestations of lipodystrophy, alopecia, skin features, and joint contractures were not affected by the drug. The authors concluded that this preliminary study suggested that lonafarnib may have a therapeutic benefit for HGPS patients, but acknowledge that the study was limited by its observational design. (3)

In vitro studies are ongoing. Everolimus has been applied to fibroblast cell lines from six laminopathy patients, each with a different mutation in LMNA; increased proliferative ability and delayed senescence was observed in all cell lines. A significant improvement in nuclear blebbing (a cellular hallmark of HGPS) was noted. (5) The balance of the A-type lamins is controlled by the RNA-binding protein SRSF1. Metformin has been demonstrated to decrease SRSF1 and progerin expression in mesenchymal cells derived from HGPS-induced pluripotent stem cells, suggesting its potential therapeutic value in affected patients. (6)

Understanding orphan diseases such as HGPS provides unique insights into mechanisms that may be applicable to the general population. Perhaps the use of farnesyl transferase inhibitors will have value for patients with cardiac, neurologic, or peripheral vascular disease. Although lonafarnib did not display direct cutaneous benefits for HGPS patients, an indirect boon to dermatologic health could occur by anti-aging effects of the circulatory system. It remains to be determined if lonafarnib (or other agents) can decelerate the aging process. I look forward to finding out.

You are all familiar with the famous quote from Robert Browning’s poem “Rabbi Ben Ezra”:
Grow old with me! The best is yet to be, the last of life, for which the first was made.
It is the last stanza, however, that I find most compelling:
So, take and use Thy work:
Amend what flaws may lurk,
What strain o’ the stuff, what warpings past the aim!
My times be in Thy hand!
Perfect the cup as planned!
Let age approve of youth, and death complete the same!

Point to remember: The farnesyltransferase inhibitor lonafarnib may lower the mortality rate in the Hutchinson-Gilford progeria syndrome.

1. Hisama FM, Oshima J. Precision medicine and progress in the treatment of Hutchinson-Gilford progeria syndrome. JAMA 2018; 319: 1663-4.
2. Dobrzynska A, et al. The nuclear lamina in health and disease. Nucleus 2016; 7: 233-48.
3. Gordon LB, eta l. Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome. JAMA 2018; 319: 1687-95.
4. Harhouri K, et al. An overview of treatment strategies for Hutchinson-Gilford progeria syndrome. Nucleus 2018 Apr 5:1-27. doi: 10.1080/19491034.2018.1460045. [Epub ahead of print].
5. DuBose AJ. Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts. Proc Natl Acad Sci 2018; 115(16):4206-11.
6. Egesipe A-L, et al. Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells. NPJ Aging Mech Dis 2016 Nov 10;2:16026.

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