It has been quite a number of years since researchers first produced dwarf mice with disabled growth hormone or growth hormone receptors, some of which still hold the record for engineered mouse longevity. Using these mice as a point of comparison to further map metabolism and aging continues to be an ongoing process, as illustrated by this open access paper. In it, the authors discuss the role of just one of many regulatory genes that might be important in many of the methods that have been used to slow aging in mice.
Cellular biochemistry is enormously complex, and thus so are the details of the changes that occur with aging, even though the underlying root causes are comparatively simple. As an analogy, consider what happens when a complicated metal assembly rusts into structural failure: rust is very simple, and that the assembly can ultimately fall apart in any one of many different ways is a function of the complexity of the structure, not of the rust. This is why attempting to slow aging by altering metabolism is so very hard and expensive, while attempting to reverse aging by repairing the root causes is comparatively straightforward and cost-effective. You can see that dynamic at work by comparing the little that has been achieved in twenty years of attempts to replicate the metabolic response to calorie restriction versus the solid progress achieved over the past five years of work on clearance of senescent cells. The latter has required a fraction of the cost and far fewer researchers than the former, while the results are already far more impressive.
Recent evidence for extragonadal actions of follicle-stimulating hormone (FSH), including effects on the function of both brown and white adipose tissue, raises the intriguing possibility that FSH may be involved in the control of aging. If confirmed, this novel action of FSH would enhance our understanding of mechanisms and trade-offs involved in the control of healthspan and longevity of homeothermic organisms. Follicle-stimulating hormone is produced by the anterior pituitary gland and acts as one of the master regulators of reproductive functions in both females and males.
Recent work indicates that FSH also acts within nonreproductive tissues, including bone. Researchers provided elegant evidence that FSH also influences adipose tissue functions; specifically, blocking FSH actions with a specific antibody stimulated thermogenesis in both brown and white adipose tissues (BAT and WAT), reduced adiposity, and increased bone mass in laboratory mice. These findings imply that the well-documented postmenopausal increase in FSH secretion is likely among the causes for increased adiposity, reduction in bone mass, and alterations in energy metabolism at this stage of life history. One could also suspect that the gradual age-related increase in FSH levels in men has similar consequences.
We suggest that the physiological changes resembling the benefits of blocking FSH action may also occur in response to a modest reduction in FSH levels in animals genetically predisposed to extreme longevity. This would imply that FSH may have a role in the control of aging. Our hypothesis that FSH may have a role in the control of aging stems from observations in two types of mice in which reduction in FSH levels, activation of BAT, browning of WAT, and increased energy expenditure are associated with major extensions of healthspan and longevity.
In Prop1df (Ames dwarf) mutants with a genetic defect in the differentiation of somatotroph, lactotroph, and thyrotroph cell lineages in the anterior pituitary, the expression of the FSH-β subunit gene, the pituitary FSH content, and the plasma FSH levels are significantly reduced. A similar reduction in plasma FSH levels occurs in both sexes of mice with deletion of the growth hormone receptor (GHR) gene (Laron dwarf). In both Prop1df and GHR-/- mice, BAT is enlarged and highly active, subcutaneous WAT exhibits characteristics of 'beiging' and metabolic rate is increased. Moreover, their respiratory exchange ratio is reduced, implying a shift in mitochondrial function toward greater utilization of fatty acids as metabolic fuel. Both Ames dwarf and GHR-/- mice are remarkably long-lived, with increases in longevity ranging from some 20% to over 60% depending on the diet, gender, and genetic background of the animal.
We have previously proposed that the activation of BAT and increased metabolic rate in these long-lived mice represent responses to increased radiational heat loss in these diminutive animal. However, results of GH replacement therapy in Prop1df mice indicate that their metabolic characteristics and extended longevity can be at least partially uncoupled from body size. Extrapolating from the recent findings noted above, we now hypothesize that reduced FSH levels in these animals may produce (or contribute to) their unique metabolic profile, and also likely to their extended longevity.
If confirmed, the effects of reduced FSH levels in these animals would represent a novel mechanism of trade-offs between their fertility and longevity. Both sexes of GHR-/- mice and male Ames dwarfs are fertile, but their sexual maturation is delayed and fecundity is reduced. Important trade-offs between reproduction and aging have been studied and discussed for decades, but our understanding of the underlying mechanisms is very limited, and in mammals, virtually nonexistent. Thus, combining the results of FSH blockage with the available information on endocrine and metabolic characteristics of two types of long-lived mice produces a novel mechanistic insight into the complex interaction of sexual maturation, reproductive effort, fecundity, aging, and lifespan.