Our findings are consonant with studies of identical and fraternal twins that show a strong effect of genetic factors on serum free thyroid hormones and TSH. These studies support the idea that the thyroid function set point between free hormones and TSH are genetically deter- mined (16). These findings were further supported in Mexican-American families in the San Antonio Family Heart Study (17), which showed that genes controlled a substantial portion of the variation in thyroid hormones and suggested that identification of such genes could pro- vide important insight into processes that modulate thy- roid hormone-related metabolic effects.

The inverse correlation between serum TSH and FT4 concentrations in our study groups raises the possibility that mild, subclinical hypothyroidism might contribute to this phenotype. Whether hypothyroidism plays a direct role in human longevity remains to be determined. How- ever, multiple animal studies have shown a cause and ef- fectrelationshipbetweenthyroidfunctionandlifespan(7, 26). There are several comparative aging studies that in- volve animals with slow rates of aging. These animals demonstrate only minimal age-related deterioration in physiological capacity and reproduction and are resistant to chronic disease (8). Indeed, extraordinary longevity in animal models may be associated with exceptional anti- agingmechanisms,providinguniqueinsightsintoboththe genetics and physiology of longevity. One example of such a mammal is the naked mole-rat (NMR, Rodentia: Bathy- ergidae; Heterocephalus glaber), which has a life span of more than 28 yr, exceeding any other rodent of its size (8). Other examples of mammal longevity are the Ames and Snell dwarf mice and calorie-restricted (CR) rats (27). In- terestingly, all of these animals exhibit at least three com- mon hormonal and metabolic characteristics: reduced thyroid function, (absent TSH and severely reduced thy- roid hormone in Ames and Snell dwarf mice, reduced thy- roid function in NMR and CR rats), reduced basal met- abolic rate, and reduced core body temperature (8, 27). A causal relationship between thyroid function and longev- itywasfurtherdemonstratedbyexperimentalinductionof hypothyroidism in rats, which resulted in extended life span. Conversely, inducing hyperthyroidism resulted in significantly shorter life span (26, 28). Taken together, animal models of longevity demonstrate that hypothy- roidism, and the accompanying metabolic consequences of hypothyroidism, play a central physiological role in life

A limitation of our study is that, at present, our findings and conclusions are restricted to the Ashkenazi Jewish population and cannot be generalized to other popula- tions. Clearly, genetic studies in non-Ashkenazi popula- tions in North America would be of great interest in this regard. Others have reported on serum TSH in individuals of exceptional longevity, some showing increased concen- trations (2, 31) and others showing decreased concentra- tions (32, 33). None have reported on genetic changes as inthepresentwork.Wesuggestthatthosereportedstudies be interpreted cautiously because the study populations were small, have different genetic backgrounds from our study groups, and live in areas of variable iodine supply. Another limitation is that, because of lack of availability of serum in some individuals, we could not examine the relationship between FT4 and TSH in the entire control and offspring groups.

In our Ashkenazi populations, the higher serum TSH concentrations in the centenarian group and their off- spring suggest that they might have a small degree of hy- pothyroidism, possibly subclinical hypothyroidism. Be- cause nonthyroidal disease may decrease serum TSH, an alternative, but less likely, possibility is that the centenar- ians were in better overall health than the control group (34). Subclinical hypothyroidism is defined as raised se- rum TSH in association with normal FT4, and it occurs in millions of people, particularly the elderly (1). The prev- alenceofTSHabove4.5mIU/literislessthan2%inpeople without known thyroid disease who are between 20 and

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