Genetic Predisposition to Elevated Serum Thyrotropin Is Associated with Exceptional Longevity
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CONTEXT: Exceptional longevity is associated with raised serum TSH. OBJECTIVE: The aim of this study was to examine whether offspring of people with exceptional longevity have elevated serum TSH and whether specific single nucleotide polymorphisms (SNPs) in the TSH-B gene and TSH receptor (TSHR) gene are associated with this phenotype. DESIGN/SETTING/PATIENTS: We measured serum TSH and free T(4) in Ashkenazi Jewish centenarians (n = 232; median age, 97 yr), their offspring (n = 366; median age, 69 yr), and age-matched controls without familial longevity (n = 163; median age, 70 yr). We determined TSH heritability, its distribution, and association with SNPs in the TSH-B and TSHR genes. RESULTS: Offspring had higher median serum TSH [1.68 mIU/liter (97.5% confidence interval, 0.65 to 4.79 mIU/liter)], compared to controls [1.50 mIU/liter (97.5% confidence interval, 0.63 to 3.93 mIU/liter); P = 0.02], with estimated heritability of 0.33 (P = 0.004). Allele frequency of two SNPs in the promoter/enhancer region of TSHR gene, associated with increased serum TSH, was higher in centenarians and their offspring compared to controls (rs10149689 G allele frequency, 0.57 and 0.53 vs. 0.48; P = 0.001 and P = 0.08; odds ratio, 1.56 and 1.22, respectively; and rs12050077 A allele frequency, 0.57 and 0.53 vs. 0.46; P = 0.0001 and P = 0.01; odds ratio, 1.68 and 1.32, respectively). Linkage disequilibrium between the two SNPs was high (r(2) = 0.95), suggesting interaction between them. Furthermore, GA haplotype frequency was significantly higher among centenarians and offspring compared to controls (0.57 and 0.53 vs. 0.46; P = 0.0001 and P = 0.01, respectively). CONCLUSIONS: A heritable phenotype characterized by raised serum TSH is associated with human longevity. Carriers of rs12050077 and rs10149689 SNPs in the TSHR have higher serum TSH, possibly contributing to decreased thyroid function and longevity.
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The distribution of serum TSH reference interval is right-shifted with age, giving an upper 97.5% confidence interval of around 7.5 mU/L in healthy elderly people.
“the distribution of serum TSH reference interval is right -shifted with age, 24 -26 giving an upper 97.5% confidence interval of around 7.5 mU/L in healthy elderly people. 2,3”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [25]
The Discussion describes a shift toward higher TSH with age, and Table 1 reports an upper 97.5% CI of 7.15 mIU/L for Ashkenazi Jewish centenarians—reasonably close to 7.5. The paper does not establish that upper limit for healthy elderly people generally; its figure comes from a group selected for exceptional longevity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSerum TSH is higher in some genetic population groups such as Ashkenazy Jews.
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [12]
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- Authors
- Atzmon, G., Barzilai, N., Surks, M. I., & Gabriely, I.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Gabriely, Ilan
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2009-12-01
- Volume
- 94
- Issue
- 12
- Pages
- 4768-4775
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2795660
- OpenAlex
- W1966433579
- Cited by
- 145
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 5 · 2020: 9 · 2019: 10 · 2018: 11 · 2017: 12 · 2016: 11 · 2015: 9 · 2014: 6 · 2013: 20 · 2012: 11
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Glenn Foundation for Medical Research
- National Institutes of Health (AG023122, RR12248)
- National Institute on Aging (AG 023122, R01AG018728, AG027734, P01AG027734, AG-18728, U19AG023122)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK20541, P60DK020541, P30DK020541)
- National Center for Research Resources (M01-RR12248, M01RR012248, RR-12248)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- exceptional longevity, centenarians, serum thyrotropin, TSH receptor gene, single nucleotide polymorphisms, Ashkenazi Jewish population, genetic susceptibility, linkage disequilibrium
- MeSH terms
- Aged, Aged, 80 and over, Aging, Female, Haplotypes, Humans, Jews, Longevity, Male, Middle Aged, Regression Analysis, Thyrotropin, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Regulatory Elements, Transcriptional
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