Cellular Nutrient Sensing and Longevity
N. Barzilai, L. Rossetti, M. Brownlee, M. Hawkins, J. Crandall
Diabetes center, Departments of Medicine and Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Belfer Bld #701, Bronx NY 10461, USA
Caloric restriction (CR) life span of animals, while in humans excess
nutrient intake is associated with the "syndrome of insulin
resistance". This syndrome represents a constellation of metabolic
defects that are important risk factors for age-related diseases. Under
normal circumstances, the deleterious effects of the excessive
availability of nutrients are countered by the prompt activation of
nutrient "counterregulatory" systems. The latter include (but is not
limited to) hypothalamic neuro-circuitries partly under the control of
leptin. The activation of these nutrient "counterregulatory" systems
should prevent the excessive storage of energy and the onset of insulin
resistance. We will demonstrate that the hexosamine biosynthesis
pathway (HBP) is a central nutrient-sensing mechanism. Activation of
HBP induces insulin resistance and regulates the secretion of several
adipose-derived peptides through (but is not limited to) glycolysation
of transcription factor SP1. We will demonstrate that: 1) Aging muscle,
independent of body fat, expresses higher levels of the end products of
HBP, supporting increased activation of this nutrient sensing pathway.
2) Challenging this pathway directly by glucosamine administration
leads to rapid peripheral insulin resistance in aging rats. 3) In
parallel, activation of the HBP increases the expression, in particular
in visceral fat, of potentially harmful fat-derived peptides associated
with insulin resistance and its syndrome. Because a chronic increase
in nutrients can directly increase carbon flux through HBP, it may have
a potential role in the metabolic syndrome of aging and on the
mechanisms mediating the beneficial effects of CR.
Key words:
caloric restriction, nutrient sensing, hexosamine biosynthetic pathway, longevity, aging
Problems or questions regarding this site should be directed to
the organiser