In bacteria, the rate of cell proliferation and the level of gene expression are intimately intertwined. Elucidating these relations is important both for understanding the physiological functions of endogenous genetic circuits and for designing robust synthetic systems. We describe a phenomenological study that reveals intrinsic constraints governing the allocation of resources toward protein synthesis and other aspects of cell growth. A theory incorporating these constraints can accurately predict how cell proliferation and gene expression affect one another, quantitatively accounting for the effect of translation-inhibiting antibiotics on gene expression and the effect of gratuitous protein expression on cell growth. The use of such empirical relations, analogous to phenomenological laws, may facilitate our understanding and manipulation of complex biological systems before underlying regulatory circuits are elucidated.

The PATCHED (PTC) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS). Functions of PTC were investigated by inactivating the mouse gene. Mice homozygous for the ptc mutation died during embryogenesis and were found to have open and overgrown neural tubes. Two Shh target genes, ptc itself and Gli, were derepressed in the ectoderm and mesoderm but not in the endoderm. Shh targets that are, under normal conditions, transcribed ventrally were aberrantly expressed in dorsal and lateral neural tube cells. Thus Ptc appears to be essential for repression of genes that are locally activated by Shh. Mice heterozygous for the ptc mutation were larger than normal, and a subset of them developed hindlimb defects or cerebellar medulloblastomas, abnormalities also seen in BCNS patients.

However, our long-lived mice are slightly larger and consume about the same or slightly more food than the short-lived controls. Indeed, longlived systemic Irs2 +/− mice are more insulin sensitive and glucose tolerant than WT mice; however, long-lived brain-specific bIrs2 +/− and bIrs2 −/− mice are insulin resistant, hyperinsulinemic, and glucose intolerant. The mechanism responsible for this disparity is unknown. Regardless, our results point to the brain as the site where reduced insulin-like signaling can have a consistent effect to extend mammalian life span-as it does in C. elegans and D. melanogaster (1, 3).As mammals age, compensatory hyperinsulinemia usually develops to maintain glucose homeostasis and prevent the progression toward life-threatening type 2 diabetes (6); however, increased circulating insulin might have negative effects on the brain that can reduce life span (4, 21, 23). By directly attenuating brain Irs2 signaling, an aging brain can be shielded from the negative effects of hyperinsulinemia that ordinarily develop with overweight and advancing age. Consistent with this hypothesis, moderate daily exercise, calorie restriction, and weight losswhich reduce circulating insulin-might increase life span by attenuating Irs2 signaling in the brain. Other strategies that improve peripheral insulin sensitivity, such as reduced growth hormone signaling, could have the same effect (5). Indeed, human centenarians display increased peripheral insulin sensitivity and reduced circulating insulin concentrations (23). Hence, we suggest that the Irs2 signaling cascade in the brain integrates the effects of peripheral nutrient homeostasis with life span.