Sunday, January 15, 2012

It's not just the genes, but it's not just the environment, either

Damien: Dr. L. Stephen Coles, M.D., Ph.D., Co-Founder of the Los Angeles Gerontology Research Group, commented today on a recent paper by the researcher Joao Pedro de Magalhaes and his colleagues, quoted below. Some of this response is compressed and technical, but I think it gives a good sense of the way in which exploratory science is beginning to unpick the locks of aging—and perhaps eventually to find a way around it by controlling the epigenetic aspects of cell growth and maintence.

Epigenetics is the cell’s control process switching on or off, or up or down, the activities of each gene. To quote the definition by Ali Shilatifard, Ph.D.: “an epigenetic trait is a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence.” As Science Daily amplifies this: “Shilatifard and colleagues have also proposed three categories of signals that operate in the establishment of a stably heritable epigenetic state. The first is a signal from the environment, the second is a responding signal in the cell that specifies the affected chromosomal location, and the third is a sustaining signal that perpetuates the chromatin change in subsequent generations.”

Dr. Coles cites Joao Pedro de Magalhaes’s paper on the genetics of aging in model organisms [1], and comments:

I believe that it provides us with a proper vision for the relation of genomics with epigenetics (Section D). I believe that it is futile to tease out the networks of gene interactions without epigenetic changes as a function of age. Epigenetics (nRNAi) is hidden in the non-coding portion of the DNA. Gene expression profiles of senescent cells are being worked out by Judy Campisi at the Buck Institute and by others. Cells with the senescent phenotype send out cytokine signals to adjacent cells in a positive-feedback loop that causes whole tissues to shut down with age, as they still take up space and consume caloric resources (oxygen and nutrients) without performing their important biological function(s). (And all of this as a defense mechanism against cancer?) Think of the heterochronic/parabiosis experiments with mice. We need to identify the cytokine network that triggers this senescent phenotype. Wellness depends on having cells that function in the manner that they did when we were young and constantly growing. The link of the genome to the onset of puberty will be a key step in this direction, since I believe it is under tight regulatory/programmatic control in the SCN (Supra Chiasmatic Nucleus); preparing to indulge in sex is the beginning of the process of senescence, in the sense of cellular turnover slows (fresh cells not keeping up with cell loss -- the Second Law of Thermodynamics [Entropy]) in which desynchronization of clocks and mitochondrial ROS take over with a net loss of vitality (fitness) as one passes through menopause/andropause and the genomic code runs out of new instructions (the pretty flower wilts, as it were). If this process is all programmed differently in different species then it is possible to contemplate reprogramming our own genomes (with artificial chromosomes) to suit our own personal agenda, as opposed to the uninspired stochastic Darwinian Agenda handed to us by Nature without our consent. Can we accept Her compelling us to become the prisoners of frail, blind, deaf, senile, and emaciated bodies just because we were tapped to enter into Her capricious n-person game? Homo sapiens are now at a stage in which we have figured out how avoid being consumed by other creatures/predators who would seek to eat us for lunch (that took a few hundred thousand years). But our present human condition still remains as Shakespeare poetically phrased it in Macbeth (Scene V)...  

Tomorrow, and tomorrow, and tomorrow
Creeps in this petty pace from day to day
To the last syllable of recorded time;
And all our yesterdays have lighted fools
The way to dusty death. Out, out, brief candle!
Life's but a walking shadow, a poor player
That struts and frets his hour upon the stage
And then is heard no more. It is a tale
Told by an idiot, full of sound and fury,
Signifying nothing.

Not if we can engineer our way around it, it won't signify "nothing."      I put in a link on the website to your Table of the more than 20 companies worldwide that are focusing specifically on the aging process [2]. Also, thank you for your continuing to maintain the GenAge data base [3] of more than 700 genes that have been identified that regulate lifespan in model organisms across several metabolic pathways (TOR, SIR-2, SCH-9). This is a data base that I expect will expand considerably in the next five years, and we need to keep it up to date for our stem-cell research collaborators and our students.

 Refs. : 1. Joao Pedro de Magalhaes, et al, "Genome-Environment Interactions That Modulate Aging: Powerful Targets for Drug Discovery," Pharmacological Reviews, Vol. 64, No. 1, pp. 88-101 (2012).

1 comment:

  1. Environment is ever important, particularly when one considers the extreme need to avoid coming between the roadway and the bottom of bus tires for example. Exercise is important, clean air and water, proper nutrition, and so on; all things we know about already and can optimize. Then, in association with environment, it is crucial to be very, very lucky.

    Genes are another thing altogether. In spite of how much we think we know, we know practically nothing. One thing we do know, however, is that genes don't take direct actions to kill us; at worst, they just stop bothering to work so hard toward keeping us alive beyond a certain point. That can be fixed, and at some point, it will be (interesting work to that end is already in the can, at least for mice). Naturally, it will probably come too late for us older than, say, 30 years, unless we can stay VERY, VERY LUCKY!

    Gary Livick