Tuesday, November 24, 2015

Young Blood Can Reverse Aging

The quest for stopping and even reversing the aging process has entered a new phase over the past few years. A few scientists have investigated the phenomenon of administering the blood of young mice to old mice, an experiment that has a long but not a very illustrious history. As far back as the 1600s renowned figures such Andreas Libavius and Robert Boyle (of Boyle’s Law fame) proposed that transfusions of the blood of the young might rejuvenate the old, but the experiment was a catastrophe since, at the time, there was no knowledge of blood groups. 

In recent years several scientists have returned to the experiment. In 2005 Conboy et al published a paper in Nature (1) in which they used a procedure called parabiosis where they surgically combined the circulatory systems of young and old mice. Together with a later study, (2) they found that the exposure of old mice to young blood restored proliferation and the regenerative capacity of satellite cells (skeletal muscle stem cells) as well as hepatocytes (liver cells) by re-activating molecular signaling. In 2011 Villeda et al (3) demonstrated that young blood can increase regeneration of brain cells in old mice and that old blood can inhibit regeneration in young mice. This and later studies (4) showed that certain proteins in old blood decrease regeneration of brain cells in young mice and impair cognition. Specifically, they found that beta-2 microglobulin is elevated in the blood of old mice and if injected systemically, or locally in the hippocampus, impairs cognitive function and neurogenesis in young mice. The same group (5) further showed that injecting plasma of young mice into old mice can increase regeneration of cells in the hippocampus and increase cognitive function.

It is known that TGF-b1, a multi-functional cytokine, becomes elevated with age in several organs, including muscle and brain (6). Hanadie et al. (7) demonstrated that TGF-b-1 inhibition enhances neurogenesis and muscle regeneration in old mice, as well as decreasing inflammation. Sinha et al. (8) published results showing that increasing GDF-11 levels in aged mice causes increased genomic integrity of muscle stem cells and restores the structure and function of muscle cells and brain (9), though the effects of GDF-11 have recently been challenged (10). In yet another study (11), researchers found that, unlike previous theories, mitochondrial DNA is not degraded in older mice and by changing the regulation of two genes, CGAT and SHMT2, that control glycine production, they could restore mitochondrial function in fibroblast cell lines to that of young cells.

Whatever the specific molecules turn out to be, and there will eventually be several, the exciting point of all these findings is that there are elevated levels of substances in the plasma of old mice that inhibit stem cells in various organs studied, and there are other substances that are increased in young mice which promote these same stem cells. Furthermore, the stem cells of old mice can be induced to act like those of young mice by administering the correct plasma substances. If it turns out that aging can be thus reversed by common pathways in all organs systems, the cure for aging may not be far away.

But even if we isolate all these products, the question will still arise as to what genetic pathway controls their production and the aging process. It is not enough to simply administer these products to aged individuals, for practical reasons if nothing else. It will be necessary to eventually change the genome of the human species to actually make it ageless, if that is our goal. It is not a coincidence that these products are produced to induce aging. It is clear that aging, and the pace of aging, is a genetic process, since each species ages at different rates and has its own unique lifespan. Each species is programmed to self destruct after a specific period, probably related to its unique requirement to mature and reproduce at a specific rate according to its evolutionary niche (the rate at which its own unique environment changes). If the environment changes quickly – the number of predators, food supply, weather, etc.—it has to reproduce quickly, and age quickly, for its offspring to produce the mutations to adapt. Since evolution always acts through mutations on the next generation, death is a necessary evolutionary trait. The survival of the new generation, and thus the species, is greatly enhanced if the parents no longer compete for natural resources, etc. after reaching sexual maturity. For those who object by saying that few animals in the wild die of old age but rather by predation or lack of food, I ask who does the predator most likely capture? The very young are normally protected by the herd while the old and slow are the stragglers who end up as prey. Furthermore, the very young are usually fed by the parents until they are able to find food while the grandparents are left to fend for themselves. The species is programmed for the new generation to mutate into a more adapted organism and for the old, which are no longer as suited to the new environment, to die off.

If we continue on this path to cure the disease of aging, we should consider the consequences of success. Some of the positive and negative effects of creating an ageless species are obvious, and some are not. In earlier postings, I have reviewed some of these considerations, but it might be time to revisit the topic since science is moving at such a rapid rate. It seems that few people are actually discussing the practical, societal, psychological and moral issues that will inevitably arise when the cure is found.

1.     Conboy I. M. et al. Nature (2005) 433, 760-764 doi:10.1038/nature03260
2.     Brack AS, et al. Science. (2007) 317 807-810.
3.     Villeda SA, et al. (2011) Nature 477: 90-94.
4.     Smith LK, et al. (2015) Nature Medicine 21, 932-937.
5.     Villeda SA. et al. (2014) Nature Medicine 20:659-663.
6.     Carlson ME, et al. (2009) Aging cell 8:676-689.
7.     Hanadie Y. et al. (2015) Oncotarget, Vol. 6, No. 14. pp. 11959-11978
8.     Sinha M. et al. Science 9 May 2014: Vol. 344 no. 6184 pp. 649-652 DOI: 10.1126/science.1251152
9.     Katsimpardi L. Science 9 May 2014: Vol. 344 no. 6184 pp. 630-634
DOI: 10.1126/science.1251141
10.  Egerman MA et al. Cell Metabolism, May 2015 22: pp 164-174.
11.  Hashizume O. et al. Scientific Reports, 2015; 5: 10434 DOI: 10.1038/srep10434

Friday, January 30, 2015

Is Only 7% of the Human Genome Functionally Important?

ENCODE studies in 2012 (1) concluded that about 1% of the human genome codes for proteins and that about 80% of the genome is “biochemically active, and likely involved in regulating the expression of nearby genes.” These findings have produced a great deal of controversy and much hypothesizing among the scientific community. But a recent paper published in Nature Genetics (2,3) sheds doubt on those findings.

Researchers at Cold Springs Harbor created a computational method called fitCons which analyzes the changes in DNA letters that have occurred during long evolutionary periods across different species as well as during shorter periods between human individuals. In this way they hoped to identify which parts of the human genome were preserved and thus functionally important.

The present study showed that only about 7% of the letters in the human genome were preserved and are functionally important. Their conclusion is that “most of the sequences designated as ‘biochemically active’ by ENCODE are probably not evolutionarily important in humans,” and that “the much larger ENCODE-based estimates can’t be explained by gains of new functional sequences on the human lineage.”

Among the ENCODE papers, Kellis showed that 5% of the noncoding DNA is conserved across mammals and that an additional 4% is conserved among humans.

An obvious question that immediately arises if these findings are correct is what the activity shown by ENCODE in the other 73% of the genome that is not preserved by evolution is doing. Some of the critics of the ENCODE data have suggested that much of the ‘biochemical activity’ detected by their methodology is spurious and insignificant.

1.     Massachusetts Institute of Technology. "Biochemical functions for most of human genome identified: New map finds genetic regulatory elements account for 80 percent of our DNA." ScienceDaily. ScienceDaily, 5 September 2012. www.sciencedaily.com/releases/2012/09/120905154823.htm
2.     Cold Spring Harbor Laboratory. "Which 'letters' in the human genome are functionally important?." ScienceDaily. ScienceDaily, 20 January 2015. www.sciencedaily.com/releases/2015/01/150120160323.htm

3.     Brad Gulko, Melissa J Hubisz, Ilan Gronau, Adam Siepel. A method for calculating probabilities of fitness consequences for point mutations across the human genome. Nature Genetics, 2015; DOI: 10.1038/ng.3196