cation and consequences of polymorphisms in the thyroid receptor (cid:

)and (cid:

)genes. Thyroid

:

–

Peeters RP, van Toor H, Klootwijk W, de Rijke YB, Kuiper Uitterlinden AG, Visser TJ

Polymorphisms in thyroid mone pathway genes are associated with plasma TSH and

Peeters RP, van der Deure WM, Visser TJ

Genetic variation thyroid hormone pathway genes; polymorphisms in the TSH tor and the iodothyronine deiodinases. Eur J Endocrinol

Bergman A, Atzmon G, Ye K, Ma

arthy T, Barzilai N

ering mechanisms in aging: a systems approach toward the genetic component of aging. PL

Comput Biol

:e

Arnason E, Sigurgislason H, Benedikz E

Genetic of Icelanders: fact or fiction? Nat Genet

:

–

Bataillon T, Mailund T, Thorlacius S, Steingrimsson E, Rafnar the Icelandic population and the prospects for LD mapping: ence from unphased microsatellite markers. Eur J Hum Genet

–

Katoh T, Mano S, Ikuta T, Munkhbat B, Tounai K, Ando Munkhtuvshin N, Imanishi T, Inoko H, Tamiya G

isolates in East Asia: a study of linkage disequilibrium in the chromosome. Am J Hum Genet

:

–

sequences. Bioinformatics

:

–

60 yr of age and rises steeply to 15% in individuals older than 80 yr of age (1). Because of population shifts in TSH distribution to higher concentrations with age, the serum TSH of 70% of those elderly individuals with TSH above 4.5 mIU/liter, who are currently considered to have sub- clinical hypothyroidism, actually falls within their age- specific limits (4). These recent reports suggest that only a minority of elderly individuals with minimally raised se- rum TSH may have thyroid disease.

Our present findings of a genetic basis for raised TSH in the Ashkenazi population with exceptional longevity, if extended to other populations in future studies, suggest that this change could be protective and, as a corollary to that speculation, that routine levothyroxine treatment might be harmful.

Acknowledgments

The authors thank Ms. Zhao Hu and Mr. Temuri Bodagov for laboratory determinations, and Drs. Govindaraju R. Diddahally, and Swapnil Rajpathak for reviewing and commenting on this article.

Address all correspondence and requests for reprints to: Ilan Gabriely, 1300 Morris Park Avenue, Belfer Building, Suite 707,

This workwas supportedbyGrants AG-027734, AG-18728, RR-12248, DK-20541, and U19 AG023122 from the National InstituteonAgingLongevityConsortiumandbyM01-RR12248 from the National Institutes of Health and the Glenn Foundation.

Disclosure Summary: The authors have nothing to disclose.

References

Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE

Serum TSH, T(

), and thyroid antibodies in the United States population (

to

): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab

:

–

Tietz NW, Shuey DF, Wekstein DR

Laboratory values in fit aging individuals—sexagenarians through centenarians. Clin Chem

:

–

Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Fro¨lich M, Westendorp RG

Thyroid status, disability and cognitive func- tion, and survival in old age. JAMA

:

–

Surks MI, Hollowell JG

Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: impli- cations for the prevalence of subclinical hypothyroidism. J Clin En- docrinol Metab

:

–

Boucai L, Surks MI

Reference limits of serum thyrotropin (TSH) and free thyroxine (free T

) are significantly influenced by race and age in an urban outpatient practice of medicine. Clin En- docrinol (Oxf)

:

–

Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I

Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab

:

–

D, Cavalli G

Blood micronutrient and thyroid hormone concen- trations in the oldest-old. J Clin Endocrinol Metab

:

–

van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW

Thyroid hormone concentrations, disease, physical func- tion, and mortality in elderly men. J Clin Endocrinol Metab

:

–

Magr

,Muzzon

,Cravell

,Fioravant

,Buscon

,Camozzi D,Vignat

,Ferrar

Thyroidfunctioninphysiologicalaging and in centenarians: possible relationships with some nutritional markers. Metabolism

:

–

Wartofsky L, Burman KD

Alterations in thyroid function in patients with systemic illness: the “euthyroid sick syndrome.” En- docr Rev

:

–

Ooka H, Shinkai T

Effects of chronic hyperthyroidism on the lifespan of the rat. Mech Ageing Dev

:

–

Brown-Bor

M,Bor

E,Melisk

J,Bartk

Dwarfmice and the ageing process. Nature

:

Ooka H, Fujita S, Yoshimoto E

Pituitary-thyroid activity and longevity in neonatally thyroxine-treated rats. Mech Ageing Dev

:

–

Harpe

E,Seifer

L

Thyroidhormoneeffectsonmitochon- drial energetics. Thyroid

:

–

Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA

Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev

:

–

Ravagli

,Fort

,Maiol

,Nes

,Pratell

,Savarin

,Cucinotta