Fantastic voyage: live long enough to live forever. The science behind radical life extension questions and answers.

Putting an end to human aging is now becoming a reality, and immortality is no longer just a dream. Through what we are calling "Fantastic Voyage," we provide a guide to achieving life extension through various means, thereby slowing down aging and disease processes. The three components of Fantastic Voyage are: Bridge One--Aggressively applying today's knowledge. Bridge Two--Putting biotechnology, such as gene technologies, to use with therapeutic cloning and rejuvenation medicine. Bridge Three--Putting nanotechnology to use by developing a means to rebuild our bodies and brains with nanobots. Many of these technology solutions can be simulated today through the use of targeted supplements, designed to address the specific needs of an individual, such as insulin resistance, cholesterol and homocysteine levels, and inflammation. To slow aging now, we propose a program of supplementing aggressively, eating foods that impede aging and disease processes, and reversing inflammation through diet. We also provide guidance to customize each program to the specific needs of the individual. Emerging technologies in rational drug design, tissue engineering, gene therapy, and nanobots (among others) promise a future of automated life extension. The use of such technologies, and the resulting dramatic increases in productivity in all areas of human endeavor, will enable us to live in a world in which all our physical needs can be met.

Fetal-juvenile origins of point mutations in the adult human tracheal-bronchial epithelium: absence of detectable effects of age, gender or smoking status.

Allele-specific mismatch amplification mutation assays (MAMA) of anatomically distinct sectors of the upper bronchial tracts of nine nonsmokers revealed many numerically dispersed clusters of the point mutations C742T, G746T, G747T of the TP53 gene, G35T of the KRAS gene and G508A of the HPRT1 gene. Assays of these five mutations in six smokers have yielded quantitatively similar results. One hundred and eighty four micro-anatomical sectors of 0.5-6x10(6) tracheal-bronchial epithelial cells represented en toto the equivalent of approximately 1.7 human smokers' bronchial trees to the fifth bifurcation. Statistically significant mutant copy numbers above the 95% upper confidence limits of historical background controls were found in 198 of 425 sector assays. No significant differences (P=0.1) for negative sector fractions, mutant fractions, distributions of mutant cluster size or anatomical positions were observed for smoking status, gender or age (38-76 year). Based on the modal cluster size of mitochondrial point mutants, the size of the adult bronchial epithelial maintenance turnover unit was estimated to be about 32 cells. When data from all 15 lungs were combined the log2 of nuclear mutant cluster size plotted against log2 of the number of clusters of a given cluster size displayed a slope of approximately 1.1 over a range of cluster sizes from approximately 2(6) to 2(15) mutant copies. A parsimonious interpretation of these nuclear and previously reported data for lung epithelial mitochondrial point mutant clusters is that they arose from mutations in stem cells at a high but constant rate per stem cell doubling during at least ten stem cell doublings of the later fetal-juvenile period. The upper and lower decile range of summed point mutant fractions among lungs was about 7.5-fold, suggesting an important source of stratification in the population with regard to risk of tumor initiation.

Mutator/Hypermutable fetal/juvenile metakaryotic stem cells and human colorectal carcinogenesis.

Adult age-specific colorectal cancer incidence rates increase exponentially from maturity, reach a maximum, then decline in extreme old age. Armitage and Doll (1) postulated that the exponential increase resulted from "n" mutations occurring throughout adult life in normal "cells at risk" that initiated the growth of a preneoplastic colony in which subsequent "m" mutations promoted one of the preneoplastic "cells at risk" to form a lethal neoplasia. We have reported cytologic evidence that these "cells at risk" are fetal/juvenile organogenic, then preneoplastic metakaryotic stem cells. Metakaryotic cells display stem-like behaviors of both symmetric and asymmetric nuclear divisions and peculiarities such as bell shaped nuclei and amitotic nuclear fission that distinguish them from embryonic, eukaryotic stem cells. Analyses of mutant colony sizes and numbers in adult lung epithelia supported the inferences that the metakaryotic organogenic stem cells are constitutively mutator/hypermutable and that their contributions to cancer initiation are limited to the fetal/juvenile period. We have amended the two-stage model of Armitage and Doll and incorporated these several inferences in a computer program CancerFit v.5.0. We compared the expectations of the amended model to adult (15-104 years) age-specific colon cancer rates for European-American males born 1890-99 and observed remarkable concordance. When estimates of normal colonic fetal/juvenile APC and OAT gene mutation rates (∼2-5 × 10(-5) per stem cell doubling) and preneoplastic colonic gene loss rates (∼8 × 10(-3)) were applied, the model was in accordance only for the values of n = 2 and m = 4 or 5.