Hi folks… I answer questions for the Howard Hughes Medical Institute Ask a Scientist program, and it occurred to me that perhaps people here, who tend to be pretty well educated, would be interested in reading and discussing some of the questions. So, in a pilot sort of way, I thought I’d try an experimental post along these lines. (Quick disclaimer: This is not for the purpose of giving medical advice.) Today’s topic is about the aging of cloned animals.
Some cloned animals seem to age faster than normal. If the clone cells “remember” the age of the mother, the process of DNA replication through mitosis is less and less efficient (my limited understanding.) She wanted to know why single-celled organisms do not eventually produce less perfect copies, as differentiated body cells would, because they are also reproducing by mitosis.
“Answer” on the flip…
For some background information, I recommend the web page http://senescence.info/causes.html particularly the third section, animal cloning and aging. The results summarized there seem somewhat inconsistent, such that in some but not all cases of cloning has accelerated aging been observed, and the initial hypothesis for the cause of accelerated aging–telomere shortening–does not appear correct.
Baker’s yeast is the single-celled organism most intensively studied on topics of aging. There is a significant difference between a multicellular organism and a culture of unicellular organisms. The effects of aging on single cells seem to be sporadic or statistical to some degree–if you were to follow a lineage as time goes on, the number of age-related problems increase, but in a unicellular population, the phenotypically ‘aged’ cells are selected against and gradually disappear from the population (whereas in a multicellular body, the aged cells hang around for a while, and sometimes are not easily replaced when they die).
With unicellular organisms, the cells that are lucky and remain healthy reproduce the most, and this leads to a steady-state situation where some fraction of cells are constantly becoming old and being outcompeted and outbred by cells that stay young. This is particularly true in yeast because cell division/mitosis is asymmetric; one cell, called the bud cell, gets mostly newly synthesized proteins, whereas older proteins stay in the other cell. Painstaking experiments in which a scientist repeatedly separated the mother and bud after each division for many generations have shown that a mother begins to show signs of aging after about 25 divisions and usually becomes senescent (stops dividing) around 40, although there are mutations that can alter these numbers (interestingly, some mutations actually extend the ‘reproductive lifespan,’ as does caloric restriction, meaning that the food source is relatively meager–this is also true in mice). Each newly produced bud cell then becomes a first-generation mother, which will eventually become old, but not before it has produced very many brand-new bud cells itself.
So, aging does occur in this single-celled organism, but it is not readily apparent because the population is always a mix of young and old cells; the young cells reproduce, and the old cells slowly fade away. A key idea is that cell division can be asymmetric–the two cells resulting from the division are not both ‘newborn.’ I suspect that this will be a common thing in many species.
Other single celled organisms have more apparently symmetric divisions than S. cerevisiae, but recent results indicate that in the bacterium E. coli, there is more underlying asymmetry than meets the eye, and the ‘new cell’ is more reproductively successful than the old cell; the reference is PLoS Biol. 3, e45 (2005). So, there is aging, but not in a way that endangers the long-term viability of the population. This is somewhat analogous to populations of multicellular organisms, including humans–parents go to a lot of trouble to produce offspring that are brand spanking new (pun intended), and of course the offspring will outlive their parents all else being equal.
Any thoughts? Questions? Suggestions? I’d like for this to be somewhat interesting, so if this is too much above/below your level, feedback would be useful. Also, I hate to sound like I’m begging for attention, but I will be much more likely to continue this if I know there are people who are reading, so just saying that you like it would be appreciated.
sounds good to me. To much politics makes wolverine a dull boy. I’ll be reading if you’re writing–and I would say the reading level is just about right, if you’re aiming for me–bachelor’s, office working professional (funny how that sounds, writing about myself, but I guess it’s true). Thanks for the post.
Great, thanks for the feedback.
Keep it coming froggywomp. This is great. Thanks.
Recommended.
I love the content and information level is about right for me. My science level is pretty much whatever college required and a number of years of living experience.
Science and disoveries and just stuff has always fascinated me.
Keep writing and I’ll read them. I’ll try not to make lame non-science comments and try to avoid really stupid questions.
Don’t be afraid of asking “stupid” questions–my experience from teaching is that if you have a question you’d like to ask, chances are there are a lot of other people who don’t know the answer either, so everyone benefits. As long as things don’t get out of control here, I’ll do my best to answer the follow-ups (and perhaps, who knows, other people will pitch in).
Hi, Mr Ask a Scientist! That’s way cool that you’re here. HHMI is a great resource for teachers and students – I use it a lot. (I’m a biology prof at a community college.)
I usually discuss telomeres in connection with cancer, but my students connect the dots and ask about telomeres and cloned animals. I haven’t been keeping up with this. I think the last answer I gave to this question was, “Well, it’s not really clear that cloned animals are aging prematurely, and if they are, whether telomeres are an issue.” (Vague enough? Ummmm, when you don’t really know the answer, punt.) You say, “the initial hypothesis for the cause of accelerated aging–telomere shortening–does not appear correct.”
Would you be willing to give me the short version of how this hypothesis was disproved that I can share with my students next time I’m put on the spot? Thanks.
I’m going to start by quoting a bit from the link I gave early in the diary:
“…mice cloned for six generations did not live less (Wakayama et al., 2000). Clones have been produced from a 21-year old steer also using quiescent cells (Hill et al., 2000); scientists then made a new clone taking cells from the foetal clone and compared the percentage of successfully created clones: no difference was found. Scientists took cells from a 17-year old bull and allowed them to divide (Kubota et al., 2000); they then used cells at different senescence stages to create clones and amazingly it appears that the older cells are more efficient. One interesting factor was that these clones actually contained DNA damage in the form of shorter telomeres.”
To summarize, if shorter telomeres in the ‘source’ cell caused problems in clones, you would expect the clones made from ‘older’ cells to have more problems, especially age-related ones. However, this is not the case, and in the case of the Kubota paper, there was actually the reverse correlation.
I have no idea why there was a reverse correlation instead of no correlation. As to the absence of age-related problems, I speculate that perhaps shortened source telomeres do not affect clone aging because there is presumably abundant telomerase in the egg cell into which the somatic nucleus is transplanted, and thus the telomeres may be restored to ‘normal’ length. Furthermore, in telomerase knockout mice (breeding normally/sexually), problems do not begin to appear for several generations, indicating that the telomeres have quite a bit of buffer to lose before the chromosomes become distressed.
(Note that there is a poorly characterized (last time I checked) telomerase-independent mechanism presumably involving recombination called “ALT” that can maintain telomeres; hence it’s possible to have immortalized cell lines (read: cancerous or cancer-like) that lack telomerase, although these usually show some genomic instability, as expected if they have become recombination-dependent.)
get back to you. And sorry I didn’t follow the link before I asked the question. I was about to run off to class when I saw your diary. I skimmed some of the site and printed out some more to read when I have more time. Much food for thought. My first impression is that telomere shortening probably plays some role in cellular senescence, but exactly what role or how it works is unclear at present, since there’s no simple correlation between length of telomeres and cellular “age.” More clear is that any role for telomere shortening must involve interaction with other factors.
I’m intrigued by several of the things I noticed in my skimming – that telomeres may be long enough for several lifetimes, that cells from a centenarian grew in culture as well as those from younger individuals, and how in hell do you get at the question of how well in vitro reflects accurately what is happening in vivo?
Anyway, thanks so much for answering. I may be back with more questions when I have a chance to read more.
(And, btw, the “Godseed” stuff looks a little weird for my taste.)
What’s that?
On another page from the site you linked to.
Hmm… suppose I should’ve been more careful about vetting the site.
Quite interesting, a nice change of pace.
Are you sure it is not a Social Security thread in disguise? 😉
Good level for me, a bio jock out of high school who discovered in college that the philosophy classes were all in the afternoon!
How about a topic on the state of research on gene-linked pharmaceutical delivery?
I’m honestly not exactly sure what you mean by that. I’m a little familiar in a vague way with pharmacogenomics–how genotype affects response to drugs, on a genomic scale–but it sounds like you’re asking about specific genetic variation with regard to the delivery process, or how drugs get to their target site. It’s cool that you have a specific question, but I know virtually nothing about it.
S’OK, rock on with your next topic…. R
What day is it anyway? I think it just crossed over to tomorrow, and I am too brain dead to read. But I will. Read. Tomorrow.
Please keep ’em comin….
Very interesting and refreshing, I’m going to look forward to the ‘science break’ so I hope you continue! I have a lower level of education than most here, I think, but it was clear enough for me to follow.