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Published in 2001, the AREDS clinical trial reported that zinc (80 mg), copper (2 mg) and the antioxidants vitamin E (400 IU), vitamin C (500 mg) and beta-carotene (15 mg), reduced the risk of AMD progression by 25%. Because ocular disorders such as cataract, AMD and diabetic retinopathy have been reported to be significant predictors of decreased life span, AREDS investigators examined the relationship between AMD, cataract and mortality among AREDS participants. They also analyzed the relationship between mortality and the high-dose supplements used in AREDS.

Cataract and AMD Increase Mortality

At baseline, the median age of the 4757 AREDS participants was 69 years. During a median follow-up of 6.5 years, 11% of the 4753 AREDS participants died. In fully adjusted models, participants with advanced AMD had increased mortality compared with those with few if any drusen (RR 1.41), and advanced AMD was associated with cardiovascular death. Nuclear opacity (RR 1.40) and cataract surgery (RR 1.55) were also associated with higher all-cause mortality and with cancer deaths.

Supplemental Zinc Improves Survival

Participants randomly assigned to receive zinc, whether alone (RR 0.73) or combined with antioxidants (RR 0.88), had lower mortality than those not taking zinc. That represents a 27% reduced risk of mortality for zinc alone, and a 12% lower risk for those who took zinc combined with beta-carotene, vitamin C and vitamin E. This finding contrasts with that of a recent meta-analysis which linked high dose vitamin E with increased mortality (2).

The positive association of zinc with improved survival did not seem to be due to a reduction in deaths from circulatory disease or cancer. Further analysis suggested a possible protective effect for respiratory causes of death. The beneficial effects of zinc on mortality in this study may be related to an improved immune response, which is known to decline with aging.

Lower Survival May Reflect System-Wide Processes

These findings are generally consistent with other large population-based studies that have reported associations between impaired vision and increased mortality. Ocular disorders, particularly cataract, may be markers of systemic processes associated with accelerated physiologic aging and earlier death, and not just local processes. For example, generalized oxidative damage might play a role in the development of cataract as well as aging. The association noted between AMD, all-cause mortality and death from circulatory diseases may be explained by an underlying vascular basis for AMD, a hypothesis suggested by some epidemiologic studies.

This is the first large randomized trial to report a benefit of high doses of zinc on survival, though other researchers have reported that moderate zinc and selenium doses improved immunity and resistance to infections in the elderly. More randomized trials of supplemental zinc and mortality are needed to confirm these findings.

Graphic courtesy of Archives of Opthalmology

References

1. AREDS Research Group. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study. AREDS Report No. 13. Arch Ophthalmol. 122:716-726, 2004.
2. Miller ER et al. Meta-analysis: High-dosage vitamin E may increase all-cause mortality. Published online Ann of Intern Med, Nov. 10, 2004.