Effects of Glycoxidative Stress on Human Aging

Advanced glycation products or AGEs are a heterogeneous group of molecules formed by exposure of tissue constituents to high levels of reducing sugars, e.g. glucose. The interaction of these compounds with extra- and intra-cellular components may account in part for several conditions related to aging. It has recently been recognized that AGEs are also formed during the preparation of food by heating, are absorbed into the circulation and become largely incorporated into tissue components. Accumulation of these exogenous substances over time may, together with those generated endogenously, contribute to the clinical manifestations and complications of aging.

This is an interventional-randomized study in which we are trying to determine whether a diet low in AGE can effectively reduce circulating AGE levels, with or without altering oxidation or inflammatory markers, in a subset of both young and older subjects , over a period of 4 months. If positive results are obtained, longer-term prospective studies will be designed to determine if this intervention can affect disease outcomes in older age subjects.

The study design is very simple and consists initially of obtaining a dietary history, a blood sample, 24-hour urine collection and, subsequently, of determining the effects of a low-AGE diet for 4 months on the plasma levels of these compounds in a group of healthy subjects.

Advancing age is known to be associated with increased oxidant stress (OS), increased prevalence of cardiovascular disease, impaired glucose tolerance, diabetes mellitus, decline of renal function, and accumulation of advanced glycation end products (AGEs). AGEs can lead to activation of transcriptional pathways, excessive proliferative/growth-related phenomena and sustained inflammation and through these different mechanisms may contribute significantly to the clinical complications of aging. Recently, it has become clear that a major source of AGE precursors and OS is the Western diet. The body turnover of AGEs involves specific receptors and is also dependent on renal function.

While experimental work has linked AGE-mediated OS and chronic complications in aging animals, human studies are strikingly lacking. We plan to test the following two hypotheses: 1) older men and women (age \> 60 years) who consume standard diets (usually high in AGE content) will have higher serum levels of AGEs in conjunction with higher markers of OS, vascular dysfunction and inflammation when compared with younger subjects (age \< 35 but \>18 years), and 2) dietary AGE restriction will reduce the serum levels of AGE, markers of OS, vascular dysfunction and inflammation and attenuate the difference between older and younger groups.

Specific aims:

To determine the effect of dietary AGE modification for 4 months on circulating levels of AGEs, markers of oxidative stress, vascular dysfunction, inflammatory mediators and AGE-receptor mechanisms in PBMN in old and young subjects. This will be a randomized study (Study 2).

Eligibility Criteria:
Inclusion Criteria:

* Adult subjects of any gender or race between the ages of 18 and 35 or older than 60 years

Exclusion Criteria:

* Diagnosis of diabetes (absence of diabetes will be defined as a negative history of diabetes in combination with a HgbA1c \< 6% at the time of recruitment)
* Any major cardiovascular event (myocardial infarction, stroke, PTCA or coronary artery bypass) within the preceding 3 months
* Smokers
* Glucocorticoid, anticoagulant (except for aspirin) or antioxidant therapy
* Serum creatinine greater than 2 mg/dl
* Inability to understand or unwillingness to follow study diets
* Any severe illness with an expected patient survival less than 1 year
* Patients who have initiated therapy with ACE inhibitors, lipid lowering medications or hormone replacement within the previous 3 months. Patients on stable doses of these medications will be included
* Before randomization all subjects will be screened with a 3-day food record to determine their average spontaneous daily intake of AGEs. Only those subjects whose daily intake is on the upper half of normal (greater than 14 AGE Eq/day) will participate in the study. This value of 14 E/day corresponds to the median daily AGE intake estimated in a large number of healthy subjects.