Although oral candidiasis is frequently seen in the elderly, the factors determining candidal growth have insufficiently been explored. Hence, we examined the influence of aging on candidal adhesion and growth-inhibitory agents in saliva in 45 healthy volunteers and 60 patients with oral candidiasis. Both non-stimulated and stimulated salivary flow rates (SFRs) in the healthy controls decreased with aging. A gradual decrease of SFRs with aging was also observed in the patients, and the SFR levels were markedly lower than those in the controls. Although the salivary glucose levels were almost constant in all age groups, secretory immunoglobulin A and lactoferrin levels in saliva were significantly decreased statistically with age, and a marginal age-associated decrease in transferrin levels was also observed. In addition, the generation of superoxide from neutrophils in saliva and their Candida killing activity decreased with age, and these phenomena were more apparent in the patients. Furthermore, a larger number of Candida adhered to oral keratinocytes obtained from the elderly healthy controls than to those obtained from young controls. Correspondingly, keratinocytes from the aged controls showed more concanavalin-A binding sites than those from the young controls. However, oral Candida did not increase with increasing age in the controls, although an age-associated increase of oral Candida was observed in the patients. Taken together, these results indicate that the decreases of SFRs and salivary anti-candidal factors, suppression of salivary neutrophil function and the increase of candidal adhesion sites on keratinocytes predispose elderly individuals to oral candidiasis.

To develop a new strategy to control candidiasis, we examined in vivo the anticandidal effects of a synthetic lactoferrin peptide, FKCRRWQWRM (peptide 2) and the peptide that mimics it, FKARRWQWRM (peptide 2). Although all mice that underwent intraperitoneal injection of 5 ؋ 10 8 Candida cells with or without peptide 2 died within 8 or 7 days, respectively, the survival times of mice treated with 5 to 100 g of intravenous peptide 2 per day for 5 days after the candidal inoculation were prolonged between 8.4 ؎ 2.9 and 22.4 ؎ 3.6 days, depending on the dose of peptide 2. The prolongation of survival by peptide 2 was also observed in mice that were infected with 1.0 ؋ 10 9 Candida albicans cells (3.2 ؎ 1.3 days in control mice versus 8.2 ؎ 2.4 days in the mice injected with 10 g of peptide 2 per day). In the high-dose inoculation, a combination of peptide 2 (10 g/day) with amphotericin B (0.1 g/day) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.1 g/day) brought prolonged survival. With a combination of these agents, 60% of the mice were alive for more than 22 days. Correspondingly, peptide 2 activated phagocytes inducing inducible NO synthase and the expression of p47 phox and p67 phox , and peptide 2 increased phagocyte Candida-killing activities up to 1.5-fold of the control levels upregulating the generation of superoxide, lactoferrin, and defensin from neutrophils and macrophages. These findings indicated that the anticandidal effects of peptide 2 depend not only on the direct Candida cell growth-inhibitory activity, but also on the phagocytes' upregulatory activity, and that combinations of peptide 2 with GM-CSF and antifungal drugs will help in the development of new strategies for control of candidiasis.