Genetics of Anti-Aging

ertwro (62)in #science • 7 years ago (edited)

TL;DR It seems there are genetic regulatory pathways for aging. Some individuals have expressed mutations that favor maintenance and longevity. In normal individuals environmental stress particularly caloric restriction seems to inhibit those pathways leading to more longevity.

One of the great notable differences about animals of the same size is their lifespan. A mouse is similar in size and shape to a bat but the bat's lifespan is 25x that of the mouse. On the other hand, how does an animal as big as a whale reach 200 years? The reason for this seems to be that they have different genes.

If you take an animal with a relatively short lifespan whose DNA is well known by researchers then if in the same species there are longevity differences those must have alterations. This seems easier than comparing one animal to another. The logic of this is that if there are points of regulation in genes for aging, then producing an animal that could live longer is possible.

This was tested in a worm called C. elegans. Their lifespan is close to two weeks after hatching. It didn't take long before a mutant variation that already lived to 30-50% longer than a normal worm was found.

A mutation identified like DAF-2 doubled the lifespan of the worms that had it.¹ As shown by the graphic, by day 30 in the wild type are all dead but the in the mutant above 80% are still alive and thriving at the same time.

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To put it into perspective. A single mutation made the worm equivalent of a 90-year-old human behave like one in its late 20's.

The DAF-2 gene encodes a hormone receptor, is a membrane receptor and its stimulation speeds up aging. This receptor is similar to two hormone receptors in humans: The receptors for insulin and IGF-1 ² these receptors signal the uptake of energy and growth.

This actually correlates well to other animals. In the case of Drosophila melanogaster³ a mutation in the gene that encodes the insulin/IGF-1 receptor results in higher longevity, which can be taken as a hint that the normally functional receptor acts as an inhibitor of longevity.

In the case of mice, the receptors are separate. If a mouse is heterozygous for the mutation of the IGF-1 receptor it still lives 20% longer. If you remove the functionality of the insulin receptor from the fat tissue the mouse lives longer and even with a high-fat diet they don't get fat. ⁴

This means is a highly likely scenario that they share a common ancestor in which this was the mechanism for controlling aging. This path can be traced further.

In the case of dogs, it has been shown that a big dog like a great Dane can live 5-7 years, while a small dog like a chihuahua can live up to 20 years (a difference of 50 times in mass for the same species). The single determinant factor for size is a single allele difference in IGF-1.⁵

^{Cover: Science Vol. 316, Issue 5821}

The effect of the homologous genes to DAF-2 have different periods of activity. In the case of Drosophila and C. elegans, there was no alteration to size to extend lifespan and since growth in most animals is not required to continue beyond a certain period. In the case of C. elegans the turn down of the DAF-2 gene by RNAi at different stages of its life and found that most of the benefit comes from turning the gene down after adulthood.⁶

Another factor identified was the presence of DAF-16 that acts as a transcription factor. In DAF-2 mutants that also lack DAF-16 the extension of lifespan is no longer functional.⁷

_{_{"Loss of daf-2 function during development
does not increase life-span. Wild-type animals were grown on bacteria expressing daf-2 dsRNA from hatching until the first day of adulthood and then transferred to bacteria expressing dsRNA of dcr-1. Red line, lifespans of wild-type animals grown on daf-2 RNAi bacteria during development and then shifted during day 1 of adulthood to bacteria expressing dcr-1 dsRNA. Blue line, life-span of wild-type animals grown on the control RNAi bacteria during development and then shifted during day 1 of adulthood to dcr-1 RNAi bacteria. Black line, life-span of wildtype animals grown on daf-2 RNAi bacteria during development and adulthood. Life-span studies were conducted at 25°C." [Source]}}

DAF-16 encodes a transcription factor that is at the end of a kinase cascade, and when phosphorylated, DAF-16 accumulates in the nucleus and seems to be the center of a cumulative cascade of regulation in other nuclear genes.

In the case of mutants with alterations for the path of IGF-1, like GH mutations, there are no significant benefits to caloric restriction as the route is already down-regulated. In mice without the alteration the caloric restriction makes them behave like the mutant.⁸

These genes seem to be an evolutionary adaptation to changing environmental conditions and means to protect the population enough to reproduce and to age shortly after resources have normalized and reproduction has been fulfilled.

As a side note: In another post, I examined briefly a type of caloric restriction diet known as intermitent fasting. There I mentioned how caloric restriction diets are the only reliable known way, applied statistically to populations to extend life. In the case of humans the official position is that concensus is that the long term effects are unknown⁹ , the benefits of this are controversial in their universality in most animals since there exist variation in response for individuals that have a genetic makeup that has alterations in this pathway.

References

1_{Cynthia Kenyon, Jean Chang, Erin Gensch , Adam Rudner and Ramon Tabtiang. A C. elegans mutant that lives twice as long as wild type. Nature 366(6454), 461-464 (1993).}

2_{Kimura, KD, Tissenbaum, H, Liu and Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942 (1977)}

3_{Tatar, M, Bartke, A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science 299. 1346. (2003)}

4_{Blüher M, Kahn BB, Kahn CR.. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003 Jan 24;299(5606):572-4.}

5_{Nathan B. Sutter, Carlos D. Bustamante et al. A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs. Science Vol. 316, Issue 5821, pp. 112-115}

6_{Andrew Dillin, Douglas K. Crawford and Cynthia Kenyon Timing Requirements for Insulin/IGF-1 Signaling in C. elegans. Science 298(5594), 830-34 (2002)}

7_{Morris, J.Z., Tissenbaum, H.A., and Ruvkun, G. (1996). A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536-539.}

8_{Luigi Fontana, Linda Partridge, Valter D. Longo. Extending Healthy Life Span—From Yeast to Humans. Science 16 Apr 2010: Vol. 328, Issue 5976, pp. 321-326}

9_{Spindler S.R. (2010) Biological Effects of Calorie Restriction: Implications for Modification of Human Aging. In: Fahy G.M., West M.D., Coles L.S., Harris S.B. (eds) The Future of Aging. Springer, Dordrecht}

Images referenced, sourced or modified from google images, labeled for reuse

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7 years ago in #science by ertwro (62)

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applelex (57) 7 years ago

How long for gene therapy? Hopefully soon :)))

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subcosmos (48) 7 years ago

Very soon. CRISPR is a hot thing right now in the biotech community at large. I need more fingers to count the number of people I know working on tools in this space. The biggest problem remains delivery into cells throughout the body.

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applelex (57) 7 years ago

Indeed, I'm waiting for gene therapy for my eyes...I use to have 20/20 vision. I think most of us constantly in front of screens is messing up our eyesight...I was looking into getting an e ink android reader for a display instead of using my phone. I started using blue light filter on my phone but still not good enough

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exercisinghealth (60) 7 years ago

Myopia or short sightedness, has become a growing problem over the past few decades. The cause is, spending too much time at a close focal length. It causes stress on the focusing muscles. The muscles eventually go into a spasm. When you then try focus far out, the muscles temporarily cannot re-focus.

This ‘blurred vision’ compels us to go to the optometrist. Instead of the good doc telling us to rest the eyes and spend some time focusing at lengthier focus lengths, they slap you with a 3oo dollar pair of spectacles.

The eye never recovers, but actually has to change its shape to accommodate the lense. A year later, your eyes have deteriorated and you repeat the process.

Here is a video of an eye specialist who exposes the truth behind short sightedness.