Do Cloned Animals Age Normally?

From the perspective of understanding how cloning affects aging, the field of somatic cell nuclear transfer is still young. Only recently has there been enough data for the longer-lived mammals to draw initial conclusions, and even then much more health and mortality data would be needed to go beyond the simple statistic of maximum observed life span. This is an area of interest to those researchers involved in mapping the detailed relationship between the operation of metabolism and the progression of degenerative aging. If it turns out that individuals of some species do not age normally as a result of being cloned, that may point to specific mechanisms in cellular biochemistry that merit a deeper investigation, especially those involved in the sweeping process of damage repair that occurs early in embryonic development, turning aged parental cells into youthful child cells.

It is a basic, yet still quite mysterious fact that at fertilization the aging clock in metazoans is "reset to zero." While every individual "ages" over time, and consequently dies at some point, the cells in the germline seem completely resistant to age-related changes - otherwise a species would age as quickly as the individual itself. While individual germ cells do age along with its organism, various control and selection mechanisms assure that the next generation starts relatively "unchanged" and healthy. It is, for example, now known that both nuclear and mitochondrial genomes are likely to acquire a small number of mutations between parents and offspring. We regard this minimal change that occurs during natural reproduction, within the physiological reproductive lifespan of the parents, as the ideal 'reset to zero' of the aging clock, against which the aging of cloned animals has to be compared.

In somatic cell nuclear transfer (SCNT), the nucleus of an adult cell is transferred to an enucleated oocyte, and is thought to not only regain pluripotency, but is also "rejuvenated" by factors in the ooplasm. Starting with works based on frogs, SCNT fully took off with the birth of Dolly the sheep. Since then, SCNT has been applied successfully in numerous species. There are relatively high losses of individuals derived from SCNT during their perinatal and early postnatal development, but they are thought to be indistinguishable from controls once they reach higher age. In fact, they are reported to have comparable performance on traits like beef and milk production. While there are clearly factors that limit the efficiency of cloning, at least some nuclei seem to be completely reprogrammed and rejuvenated to result in a completely "normal" adult individual. However, is it possible with a nucleus derived from a somatic cell, to completely start at time point zero, like gametes after a conventional fertilization? One of the biggest concerns regarding aging of cloned animals is the age of the nuclear donor cell. It was argued that if this cell is old, and consequently has shortened telomeres, the clone would already start at the age of the donor cell. However, the telomere length turned out to be at least partly restored during SCNT.

The ultimate outcome of aging is death, and therefore life expectancy is perhaps the most easily measurable parameter of aging (the question of aging can of course not be reduced to life expectancy alone). The time since several species were first cloned outdates, or is at least close to, the life expectancy of the respective species by now: goat, cattle, dog, sheep, mouse, cat, and pig. Therefore, we should be able to finally answer the question of whether at least some cloned animals can reach a life expectancy similar to that of the control animals. In several species, cloned animals reach indeed the expected lifespan. Cloned dogs seem to reach a high age. Snuppy, an Afghan hound and the first cloned dog, was 10 in 2015; and cloned female dogs of the same breed were 9. Also 3 cloned dairy goats lived to a normal age of 15 years, and Yang Yang, China's first cloned goat turned 15 in 2015. Also for cloned mice, several studies report a normal lifespan. While Dolly, the first cloned sheep, only reached 6 years, very recently, important further work on the aging of cloned sheep has been published. Thirteen aged (7-9 years old) cloned sheep, with 4 of them derived from the cell line that gave rise to Dolly, were analyzed. Detailed measurements of blood pressure and metabolism, as well as musculoskeletal tests showed no significant differences from age matched controls. Notably, these cloned sheep are already close to their typical natural lifespan. Copycat, the first cloned cat turned 10 in 2011, which is at least respectable for a cat, if still several years from the maximum lifespan. Pigs were first cloned in 2000, but the highest age reported to the best of our knowledge was 6 years.

Our own data of 33 SCNT-cloned dairy cattle show a maximum age of 14.4 years, with an average lifespan of 7.5 years. The cattle lines were discontinued in 2014 due to the end of the project. Death reasons were qualitatively not different from conventional kept cattle. This mostly anecdotal evidence shows that the aging of cloned animals seems to be qualitatively very similar or even the same as that of normal animals. Once the cloned animal has reached adulthood, most problems of the rather unspecific condition "reprogramming failure of the donor nucleus" seem to be overcome. Unfortunately, there are by far too little data available to measure possible, or even probable quantitative differences.

While the question which age cloned animals can reach is asked very often, it is surprising that actual data in the scientific literature are scarce, even about the "celebrated" first cloned animals of several species. Therefore, we had to resort to own data, personal communication and even newsletters. Nevertheless, including the very recent report about the aging of cloned sheep, it is now possible to say that at least for those species where the question of longevity of cloned animals was addressed (mouse, goat, sheep), a normal lifespan is possible. It would be interesting to find out what proportion of cloned animals indeed reaches old age, but with the current amount data it is impossible to do so. Unfortunately, research on aged cloned animals seems almost non-existent despite the public interest in various "safety" questions of SCNT. This might partly be explained by the fact that SCNT is still a very recent technique when compared to the life expectancy of most cloned species. Moreover, cloned farm animals are unlikely to be kept longer than their productive phase. Cloned sport and companion animals are mainly being kept in private care, and thus are less accessible for scientific studies. Based on the literature available so far, and also in our experience, the aging of cloned animals seems to proceed very similar to control animals. However, a thorough clinical study with a sufficient number of cloned animals, together with control animals over their entire lifespan is clearly needed for every species.

Link: https://dx.doi.org/10.1159/000452444

Comments

Mosaicism, the rearrangement of chromosomal parts, are known to accelerate aging. Mosaicism with T21-Trisomi 21 (Down syndrom) is the most common and affects 1/6 of population. 1/6 have a bit Down syndrom and I say it is the worlds biggest problem. Only future germ-line engineering can get it out of the human germ line. Those with mosaicism T21 are known to get leukaemia easier, but harder to get solid tumors. When we can make smarter humans progress in all fields will accelerate.

Posted by: Norse at November 12th, 2016 10:53 AM

Mosaicism is not the rearrangement of chromosomal parts.

Posted by: Antonio at November 12th, 2016 1:47 PM

@Antonio: Thanks. Im not educated, but have a basic understanding. Can you explain what it is.

Posted by: Norse at November 13th, 2016 1:22 PM

From wikipedia: "In genetics, a mosaic, or mosaicism describes the presence of two or more populations of cells with different genotypes in one individual, who has developed from a single fertilized egg.[1] Mosaicism has been reported to be present in as high as 70% of cleavage stage embryos and 90% of blastocyst-stage embryos derived from in vitro fertilization.[2]"

That IVF produces it is a problem and I think embryo selection is the solution. I think there should be muck more focus to get rid of mosaicism from the human germline.

Posted by: Norse at November 13th, 2016 1:27 PM

Yes, the Wikipedia definition is correct. OTOH, the human germline (eggs and sperm) can't have mosaicism, since they are single-celled. Embryos can have it, but if try to modify a pluricellular human embryo, you will probably face a huge opposition from almost everyone out there (ethicists, politicians, christians...).

Posted by: Antonio at November 13th, 2016 2:42 PM

@Antonio: This is the best answer I have received in a commentary field. I asked myself this question about if our germ cells could have mosaicism, because as you write single cells cant have it, I thought. But doctors use the word germ line mosaicism which is misleading. All children born with congenital heart failure have mosaicism and I guess that its the cause of the birth defect. When it comes to the opposition from bioethicists and other - we have to push hard forward. Biotech as an industry have to grow strong as it becomes an unstoppable force. I have all my money in BT for that reason. I encourage everybody I know planning to have a child to use embryo selection as PGD/PGS-Karyomapping and NIPT and finally ultrasound.

Posted by: Norse at November 13th, 2016 5:17 PM

Yes, as Wikipedia says, mosaicism is when an organism has different genomes in different cells of his body. It doesn't need to be detrimental. It can be, for example, that you have eyes of different color: https://en.wikipedia.org/wiki/Heterochromia_iridum

Posted by: Antonio at November 13th, 2016 5:56 PM

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