Today I’ll point out a review of one protein, pregnancy-associated plasma protein-A (PAPP-A), for which levels can be reduced or interactions inhibited in order to slow aging in mice. A decade ago, researchers claimed life extension on a par with calorie restriction in a study of mice lacking PAPP-A. More recently, evidence was assembled to show better thymic and immune function in old mice with this mutation, findings elaborated upon in a later paper. The consensus to date is that this life extension in mice is due to both lowered cancer incidence and slowed aspects of aging, and that insulin-like growth factor 1 (IGF-1) and related insulin metabolism is important in these effects. Cancer incidence is split of as it is generally considered to be only loosely coupled to aging – that it is possible to produce therapies and alterations that affect cancer rate without greatly affecting aging, and possibly vice versa. You might recall some debate along these lines for the life extension produced by rapamycin in mice.

The web of mechanisms and feedback loops that operates within a cell is enormously complex and intricate. The circulating levels of specific proteins are the switches and dials of cellular behavior, and they all influence one another, usually quite indirectly. No alteration can be made in isolation. On the other hand, that means that there are potentially dozens of feasible ways to tamper with any one core mechanism relevant to the ways in which metabolic processes determine natural variations in longevity. The challenge lies less in finding ways to modestly slow aging in laboratory animals, given that there are now scores of methodologies for slowing aging to some degree in various species, and more in understanding exactly why any particular intervention has that effect. Mapping of the links between proteins and genes and various cellular mechanisms proceeds slowly: it is an enormous job. That is one of the reasons why I’m less in favor than many of attempts to alter metabolism to slow aging. A great deal of work is required to gain the understanding needed in order to produce gains that rarely match those of calorie restriction. I’d like to see better outcomes than that in the future.

Insulin and IGF-1 are at the center of those metabolic processes and mechanisms most studied by the research community in the context of natural variations in aging and longevity. So it shouldn’t be surprising to find more links uncovered here than for other mechanisms, perhaps. Many methods that slow aging can be attributed to their influence on this slice of metabolism, and the outcomes often look very similar to the beneficially altered metabolic state produced by the practice of calorie restriction. Some decades from now, once the dust has settled and much more of cellular metabolism has been comprehensively mapped, it will be interesting to see just how many of today’s long-lived mutant lineages are in fact long-lived because their altered biochemistry involves some facet of the underlying cellular reaction to starvation. Today the map isn’t good enough to answer that question all that well. But is this all, PAPP-A and similar methods, worth chasing with major investments in medical research? If you think that calorie restriction mimetics are a good thing, then perhaps. But this isn’t the path to rejuvenation after the SENS vision for repair of the causes of aging, and not an approach capable in principle of radical life extension of decades and more. If you aim for small gains, small gains tend to be what you achieve at the end of the day.

PAPP-A: a promising therapeutic target for healthy longevity

The main known function of PAPP-A is to increase local IGF bioavailability through cleavage of inhibitory IGFBPs, in particular IGFBP-4. Indeed, PAPP-A is probably the only physiological IGFBP-4 proteinase. PAPP-A-induced enhancement of local IGF action through proteolysis of IGFBP-4 has been demonstrated in vitro and in vivo in several different systems. Reduced IGF signaling has been associated with longevity and increased healthspan. Therefore, a reduction in PAPP-A proteolytic activity represents a novel approach to indirectly decrease the availability of bioactive IGF. For therapeutic intervention, such a strategy is expected to moderately restrain IGF signaling and hence cause fewer adverse effects compared to direct inhibition by targeting the IGF receptor.

Both male and female PAPP-A knockout (KO) mice on chow diet live 30-40% longer than wild-type (WT) littermates, with no secondary endocrine abnormalities. Circulating levels of growth hormone (GH), IGF-I, glucose, and insulin were not significantly different between PAPP-A KO and WT mice in this study. PAPP-A KO mice also live longer when fed a high fat diet starting as adults. Thus, PAPP-A deficiency can promote longevity without dietary restriction. Furthermore, this extended lifespan is not a secondary consequence of a small body size because PAPP-A KO mice rescued from the dwarf phenotype by enhanced IGF-II expression during fetal development retain their longevity advantage. Finally, conditional knockout of the PAPP-A gene in adult mice also resulted in a 20% extension of lifespan. End-of-life pathology showed delayed occurrence of fatal neoplasias and indicated decreased incidence and severity of conditions with age-related degenerative changes, such as cardiomyopathy, nephropathy, and thymic atrophy in PAPP-A KO mice compared to WT littermates.

Several mouse models with reduced GH-stimulated IGF-I expression by liver and low levels of circulating IGF-I (Snell, Ames dwarf, GH receptor KO) have also been found to have extended longevity. On the other hand, transgenic mice over-expressing GH exhibit a shortened lifespan. It is important to note that PAPP-A KO mice have normal levels of circulating IGF-I (and GH) and their phenotype reflects reduction in local IGF action. Unlike the GH mutant mice that have postnatal growth retardation, deletion of the PAPP-A gene manifests itself early in fetal development as proportional dwarfism. The lifespan extension in the Snell, Ames dwarf, and GH receptor KO models reflects GH tone rather than IGF-I bioavailability.

Low circulating PAPP-A has been associated with adverse effects on placental function and fetal growth in humans. Although the role of PAPP-A in human pregnancy is not understood, PAPP-A is believed to be important for placental development. Therefore, targeting PAPP-A during human pregnancy is not likely to be a viable strategy. The involvement of PAPP-A in normal tissue repair processes also suggests a possible need to suspend PAPP-A targeting temporarily during such conditions. For example, PAPP-A increases bone accretion primarily by increasing IGF bioavailability important for prepubertal bone growth. Fracture repair in PAPP-A KO mice is temporally compromised, but not prevented from normal resolution. Similarly, controlled increases in PAPP-A expression are seen in healing human skin, indicating that wound healing may be delayed as a consequence of PAPP-A targeting.

Experimental evidence is accumulating that inhibition of PAPP-A has the potential to promote healthy longevity. It is clearly advantageous that targeting of PAPP-A has the benefit of a single intervention that affects multiple adverse changes with age, not just a single condition. PAPP-A is present in the extracellular environment, and its activity is therefore amenable to pharmacologic intervention. Strategies to inhibit PAPP-A have recently been developed and tested in experimental models. Rather than the active site of PAPP-A, a unique substrate-binding exosite, critical for proteolytic cleavage of IGFBP-4, is targeted. This efficiently eliminates activity toward IGFBP-4, but does not interfere with cleavage of other possible substrates of PAPP-A. Inhibition will target discrete conditions with increased PAPP-A activity, resulting in moderate restraint of IGF signaling and minimizing side effects. However, much remains to be learned about stages in life at which mice, and possibly humans, are susceptible to improvements in long-term health by manipulation of PAPP-A.

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