While the causes of aging are comparatively well mapped, supported by a great deal of solid evidence, the field more than ready for the development of rejuvenation therapies to begin in earnest, the biochemical details of the progression of aging remains a vast and poorly explored forest. This is also true of cellular metabolism as a whole: to fully understand aging, one must fully understand the inner workings of the cell to the finest level of detail. The research community is a lifetime removed from that goal, even taking into account a rapid pace of future progress in the capabilities of biotechnology.
Still, some parts of the overlap between aging and the operation of metabolism are mapped, at least at the high level. One of the most explored areas relates to the control of growth, the relationships between insulin, insulin-like growth factor 1, growth hormone, growth hormone receptor, and a broad collection of related proteins. Many of the earliest approaches to slowing aging via genetic engineering used these mechanisms. It remains the case that lineages of dwarf mice, engineered to exhibit disabled growth signaling, still hold the record for longevity in that species, living 70% or so longer than their unmodified peers.
Despite this record, modification of growth signaling is a false grail. Alongside research into the mechanisms of calorie restriction, it has led the research community to expend enormous effort on approaches that are technically challenging, make slow progress, and cannot greatly extend the healthy human life span. If billions in funding and entire scientific careers are to be spent on attempts to treat aging as a medical condition, why work on approaches that are incapable of producing more than a few extra healthy years? We know what disabled growth hormone signaling can achieve in humans: the small Laron syndrome population don't live appreciably longer than any of the rest of us, and suffer a range of undesirable side-effects. Perhaps they exhibit a lower incidence of cancer and diabetes, but not so much lower that it leaps out of the data. Or consider the size of life span differences between short people and tall people; it isn't large.
This is the great roadblock for all of the more established ways to alter metabolism in order to reach states in which aging is slowed, whether by disabling growth signaling or via calorie restriction mimetics. The effects are sizable in mice, and tiny in humans. The longer-lived the species, the less plastic its lifespan in response to metabolic changes induced by the environment, or through engineered genetic alterations that touch on the same regulatory mechanisms. This is a dead end, and is not where the research community should focus if the goals are rejuvenation and sizable extension of life span.
Much of the work in our laboratory during the last 30 years was directed at identifying mechanisms of extended longevity of mice with growth hormone (GH)-related mutations and answering the question how major reduction or absence of normal endocrine signals can have major beneficial impact on healthspan and lifespan. Both GH-deficient and GH-resistant mice have many phenotypic characteristics that presumably account for, or contribute to, healthy aging and extended longevity and, thus, represent likely mechanisms of these effects.
These characteristics include increased resistance to multiple stressors such as free radicals and toxins, reduced chronic low grade inflammation, senescent cell burden, and expression of pro-inflammatory cytokines in the central nervous system, reduced mTORC1 and increased mTORC2 signaling, as well multiple adaptations of carbohydrate, lipid, and energy metabolism. Many of the physiological characteristics of GH-related mutants interact, forming a complex network of mechanisms.
For example, reductions in the levels of pro-inflammatory cytokines, the number of senescent cells, the secretory capacity of pancreatic beta cells, and mTORC1 signaling, interact with increased levels of adiponectin and reduced GH signaling to improve insulin sensitivity, while each of these factors also influences aging by other mechanisms. We believe that the remarkable extension of longevity in mice with genetic GH deficiency or resistance results from alterations in multiple mechanisms of aging and interactions among these alterations.
Reduction of insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) extends the lifespan of various species. So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone (GH), IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate. The gene expression profiles of these mice models have been measured to identify their longevity mechanisms.
GH signal-deficient mice, including Snell, Ames, Little, GHR-/- , and Fgf21 Tg dwarf mice, showed increased lifespans and smaller body masses than wild type (WT) mice. Therefore, body size was strongly dependent on GH action. This consistent trend suggests an inverse correlation between size and lifespan. However, small size can not be used as a general indicator of longevity, because Kl Tg, Irs2 +/-, p66 Shc-/-, and mtor +/-; mlst8 +/- mice had normal body masses like WT mice, but showed longer lifespans than WT. In addition, GHA Tg mice had normal lifespans like WT mice, and Kl -/- and Irs2 -/- mice showing dramatically shorter lifespans also had a dwarfism phenotype. Therefore more work is needed to elucidate factors contributing to the lifespan of these mice.