Manipulation of Lamins Can Extend Life as Well as Shorten It
Permalink | View Comments (1) | Post Comment | | Posted by Reason

Hutchinson‐Gilford progeria syndrome (HGPS, or just plain progeria) is perhaps the best known of the rare but striking accelerated aging conditions caused by genetic mutation. These are not in fact accelerated aging, despite the apparent outcome, but rather DNA repair deficiencies. The water is always muddy when talking about damage and aging, however. Aging is just an accumulation of damage, and progeria is perhaps best thought of as an ordinarily fairly unimportant aspect of aging run amok to create a great deal of damage and dysfunction in cells and tissues.

Over the past decade or so researchers have come to a good understanding of the cause and mechanisms of progeria. An otherwise minor mutation in the LMNA gene leads to the generation of broken forms of a vital cellular structural protein, lamin A, and things go downhill from there: a progeria patient's cells are greatly malformed and perform poorly at the most crucial of their tasks. Interestingly, dysfunctional forms of this protein show up in small but increasing amounts over the course of normal aging, and are thought to be just as harmful - but on a much smaller scale, producing a much smaller detrimental effect. This has yet to be proven conclusively or quantified in any useful way, however.

To draw a perhaps overly simplistic analogy, if aging is running low on oil in your engine, then progeria is having a hole in your oil tank. They are similar in the sense that the end result is similar, and they share commonalities in their progression, but the root cause is completely different - and in the case of the hole in the tank, the unfortunate end result arrives a lot more rapidly. Knowing how to fix holes in oil tanks does nothing for efforts to make oil use more efficient, and it isn't of much help when it comes to repair efforts for the vast majority of engine-owners as they won't suffer oil tank holes.

It is an open question as to the degree to which small amounts of malformed lamin A contribute to degenerative aging, or even whether it is a cause or secondary effect of other forms of cellular and molecular damage that accumulate over time. The research linked below doesn't answer that question, but it certainly makes the whole area of lamin studies much more interesting - as is always the case if you can demonstrate extension of life in mice:

Antagonistic functions of LMNA isoforms in energy expenditure and lifespan

Alternative RNA processing of LMNA pre‐mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson‐Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging.

Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals.

It isn't at all clear as to how exactly the different lamins are involved in generating or avoiding this extension of life, given the resulting alterations in all sorts of interdependent aspects of metabolism, but I'm sure that other researchers will look in on this in the years ahead.

Comments

Hey there, it's always nice to see some good science-based journalism. I just have one little nitpick: progeria is not considered to be due to accumulation of DNA damage, but malfunctions in cell division caused by an aberrant nuclear structure or direct changes in gene expression. Progeria patients experience some of the diseases associated with aging (heart disease and osteoporosis) but not those caused by wear and tear/DNA damage (cancer, arthritis, dementia).

Posted by: Ymata at April 27, 2014 4:48 PM
Post a comment; thoughtful, considered opinions are valued. Please note that comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted. Note that there is a comment feed for those who like to keep up with conversations.









Remember personal info?