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Scientists have seen that knocking out different genes in mice can add longevity to one sex but not the other, and that males in twin studies have shorter telomeres — a sign of shorter cellular lifespan — compared to females.

The Secret to a Longer Life? Be Female

Human supercentenarians share at least one thing in common — over 95 percent are women. Scientists have long observed differences between the sexes when it comes to aging, but there is no clear explanation for why females live longer.

A special issue of Cell Stem Cell, June 4, 2015, includes a collection of reviews and perspectives on the biology of aging.

In a discussion about stem cell behavior and sex, Stanford University researchers Ben Dulken and Anne Brunet argue it's time to look at differences between men and women and their cell regeneration. Such research could help explain how the hormones estrogen and testosterone, influence lifespan.

It's known that estrogen directly slows the increase of blood stem cells (very helpful during pregnancy) in female mice, but also helps increase the capacity of brain stem cells at the height of estrus. Whether these changes have a direct impact on lifespan needs to be examined. Recent studies have already found estrogen supplements increase the lifespan of male mice, and that human eunuchs live about 14 years longer than non-castrated males.

Scientists have seen that knocking out different genes in mice can add longevity benefits to one sex but not the other, and that males in twin studies have shorter telomeres — a sign of shorter cell lifespan — when compared to females.

"It is likely that sex plays a role in defining both lifespan and healthspan. As the search continues for ways to ameliorate the aging process and maintain the regenerative capacity of stem cells, let us not forget one of the most effective aging modifiers: your sex."

Stem Cell Aging and Sex: Are We Missing Something?

Abstract
Longevity differs between sexes, with females being longer-lived in most mammals, including humans. One hallmark of aging is the functional decline of stem cells. Thus, a key question is whether the aging of stem cells differs between males and females and whether this has consequences for disease and lifespan.

Modeling Aging in a Dish

One of the problems with modeling genetic diseases in a dish using stem cells is that those cells are not the same age as the cells within patients with the disease being studied.

You could take skin cells from a 65-year-old patient with ALS, reprogram them into induced pluripotent stem cells (iPSCs), and then differentiate the iPSCs into neurons, but those neurons will be just a few weeks old. Such reprogrammed stem cells are known to rejuvenate metabolism, be decreased in DNA damage, and have longer telomeres than the mature cells they are from. When that's the case, what's in the dish may not be a precise representation of what's in the patient.

Memorial Sloan Kettering Cancer Center scientists Lorenz Studer, Elsa Vera, and Daniela Cornacchia reviewed strategies to advance the clock in stem cells and recreate actual late-onset conditions. In one example research groups use small molecular screens to speed up human embryonic stem cell differentiation. However, such methods do not produce mature cells. To create iPSCs, labs stress cells by exposing them to toxins, or turn on genes known to cause diseases of premature aging.

"The ability to direct both cell fate and age in iPSC-derived lines will allow modeling of human disorders with unprecedented precision. Such studies could yield more relevant disease models and define new classes of therapeutic compounds targeting age-related cell behaviors. The ability to program and reprogram cellular age on demand will present an important step forward on the road to decoding the mystery of aging."

Programming and Reprogramming Cellular Age in the Era of Induced Pluripotency

Abstract
The ability to reprogram adult somatic cells back to pluripotency presents a powerful tool for studying cell-fate identity and modeling human disease. However, the reversal of cellular age during reprogramming results in an embryonic-like state of induced pluripotent stem cells (iPSCs) and their derivatives, which presents specific challenges for modeling late onset disease. This age reset requires novel methods to mimic age-related changes but also offers opportunities for studying cellular rejuvenation in real time. Here, we discuss how iPSC research may transform studies of aging and enable the precise programming of cellular age in parallel to cell-fate specification.

A Theory for Why Germ (Sex) Cells Don't Age

A difference exists in metabolism between cells that make up your body and those we use for reproduction (germ cells that become sperm and eggs). The former are subject to aging while germ cells are seemingly "immortal."

Stem cells make energy by breaking down sugar, which is less efficient and leads to more mutations than what germ cells do — obtain energy though mitochondrial respiration.

In his opinion piece on stem cell maintenance and aging, Columbia University's Hans-Willem Snoeck makes a case that from an evolutionary perspective, stem cells don't need to last forever; they only need to get an organism to reproductive age.

Stem cells accumulate DNA damage over time. Although they repair themselves, they begin to function at a lower and lower capacity. Germ cells, on the other hand, are selected so that only the fittest will be used for reproduction. Snoeck argues that two very different ways of generating energy may underlie the difference between maintenance of stem cells and selection in germ cells.

How cells use nutrients has been connected with longevity before. It's widely reported that caloric restriction in mammals, worms, and other animals can boost lifespan.

Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline?

Abstract
The mechanisms underlying the aging process are not understood. Even tissues endowed with somatic stem cells age while the germline appears immortal. I propose that this paradox may be explained by the pervasive use of glycolysis by somatic stem cells as opposed to the predominance of mitochondrial respiration in gametes.

Cell Stem Cell, published by Cell Press, is a monthly journal that publishes research reports describing novel results of unusual significance in all areas of stem cell research. Each issue also contains a wide variety of review and analysis articles covering topics relevant to stem cell research ranging from basic biological advances to ethical, policy, and funding issues. For more information, please visit http://www.cell.com/cell-stem-cell. To receive media alerts for Cell Stem Cell or other Cell Press journals, contact press@cell.com.

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