Less Frailty in Ames Dwarf Mice and Calorie Restricted Mice

Ames dwarf mice are genetically engineered to lack growth hormone, and as a result are small, comparatively vulnerable to cold, and live much longer than their peers. The biochemistry of these mice has a number of similarities to that of calorie restricted mice, who also live much longer than their peers. Study of these and other forms of long-lived mice is shedding light on an overlapping collection of mechanisms that link the operation of metabolism with differences in the pace of degenerative aging. The hope here is that at some point this will lead to therapies to produce similar benefits in we humans, but most researchers think that such a result is comparatively distant from where we are now. The changes produced in mice through either growth hormone knockout or calorie restriction are sweeping, and it will be challenging to prove that any artificial alteration of human metabolism on the same scale is safe over the long term.

Nothing is stopping you from practicing calorie restriction, of course, and indulging in your own self-created sweeping and beneficial change to the operation of your metabolism. The human studies show that the benefits to a basically healthy individual exceed any other presently available strategy for improving long-term health. But the rules and chances of a positive outcome are very different when you want to try altering human genes and biological processes with medical technologies. Nonetheless, the enumerated benefits are good enough to keep research funds flowing, albeit at a very low level in comparison to fields such as stem cell medicine or cancer research.

Prevention of Neuromusculoskeletal Frailty in Slow-Aging Ames Dwarf Mice: Longitudinal Investigation of Interaction of Longevity Genes and Caloric Restriction

The hypopituitary Ames Dwarf Mouse was the seminal example of single-gene regulation of mammalian longevity. They are deficient in the production of growth hormone (GH), thyroid stimulating hormone, and prolactin. The deficiency in somatotrophic signaling results in mice that are approximately half the size (length or weight) of their littermate controls. These mice outlive their normal littermate counterparts by approximately 40-60%. These results of longevity have been confirmed on different diets, on different genetic backgrounds, and in independent laboratories utilizing differing animal husbandry conditions. Furthermore, multiple other growth hormone signaling-deficient mouse mutants exhibiting longevity have since been reported.

Studies dating back a century have reported the healthspan and lifespan benefits of diets restricted in caloric content yet sufficient in macro- and micro-nutrients. These diets of "undernutrition without malnutrition" have been documented to have the ability to slow the progression of aging in multiple organ systems and in multiple species. Of particular note to this study, caloric restriction (CR) increases circulating GH levels in rats, dogs, and humans. To date, few reports have investigated the effects of this feeding paradigm on functional metrics of physical function.

The vast majority of studies on neuromusculoskeletal functioning in experimental gerontology deal with charting the prevalent, well-documented, aging-associated decline in neuromuscular or skeletal structure, strength, quality or performance. Save for studies with CR animals or on exercising animals, evidence of genetic or environmental factors that might improve physical functioning is limited; and, to the best of our knowledge, no combinatorial analysis of the interaction of two different factors has been conducted.

In this study, we conducted a longitudinal investigation of the individual and combined effects of Ames dwarfism or CR on measures of neuromusculoskeletal ability in senescing mice. Our initial hypothesis was that mice deficient in an anabolic process, such as GH signaling, would be inferior in performance on tasks requiring an integration of nervous, muscular, and skeletal systems' functions; as GH is crucial to the ontogeny and maintenance of those physiological systems. Thusly, we hypothesized that GH signaling-inhibiting Ames dwarfism will correlate with impaired function on late-life neuromusculoskeletal tasks, whereas GH signaling-enhancing CR will accentuate that performance. Our overall aim of revealing differences in physical capability between slow-aging mice and their normally aging counterparts was achieved for grip strength, balance, agility, and motor coordination; yet, some results ran counter to our hypotheses.

Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age.

From this longitudinal study, we report beneficial effects of either [dwarfism], caloric restriction, or both for physical functioning in aging mice. The individual effects of either factor, in combination with the additive effects seen during the motor coordination and agility testing, suggest that it is not merely a change in body composition (as CR reduces adiposity and Ames dwarfism increases it), difference in size (as CR mice are just as long as their ad-libitum-fed counterparts), or uniqueness of experimental design (as the three tests exerted considerably different challenges on the animals) that results in the benefits seen. Rather, we posit that the decrease in the rate of senescence induced by either factor is primarily responsible for the retention of neuromusculoskeletal function observed.

For many researchers the grail is to find ways to slow aging through medicine, to reproduce the reduction in the rate of senescence noted above. This will extend human life and push back the degenerative conditions of aging. It is also, unfortunately, a slow and expensive path forward that cannot ultimately produce therapies capable of rejuvenating the old - only therapies that slightly slow the pace at which the young become old. If these therapies only emerge when we are old, then it will be too late for us.

So this is not the path that the research community should take. Something different is needed for the decades of research that lie ahead, a research program more likely to result in actual rejuvenation of the old, and soon enough to matter.

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