ITP lifespan extension study brings mixed bag of results for longevity drugs.

The long-awaited results of the National Institute on Aging Interventions Testing Program‘s look at a series of compounds to examine them for life-extending properties in mice have been released.

Longevity.Technology: Research history is littered with examples of drugs that prove effective in mice, yet have fail in humans. Felipe Sierra, the Director of the Division of Aging Biology at the NIA once stated: “The bottom line is I don’t try any of these things. Why don’t I? Because I am not a mouse.” Extrapolating data from murine models walks a path between two looming truisms: mice are not humans, but mice are still far more like humans than fruit flies, roundworms or yeast.

Despite its limitations and evidence of poor correlations with humans, the mouse is still the most commonly used model organism in human disease research. In advancing geroprotective therapies to human trials, or dismissing them as generally ineffective, extensive mouse data will be required. To move research forward, the NIA’s ITP is a multi-institutional study that is investigating treatments that have the potential to extend lifespan and delay disease and dysfunction in mice. (Do check out our wonderful video on the ITP by The Sheekey Science Show!)

Looking at the latest ITP paper, 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex, there is a lot to unpack and discuss, especially as nicotinamide riboside is such a headline-maker, and no doubt, many eminent scientists will offer their opinions.

So, as a precursor (the mot juste!) to the more detailed discussion, here are some of the key points we feel our readers should consider:.

• The interventions studied were:
  • The “non‐feminizing” estrogen, 17‐α‐estradiol (17αE2)
  • Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+)
  • Candesartan cilexetil (CC), an angiotensin‐receptor blocker used as a treatment for hypertension
  • Geranylgeranylacetone (GGA), a heat shock proteins (HSP), used as a treatment for peptic ulcers
  • MIF098 ((3‐(3‐hydroxybenzyl)‐5‐methylbenzo[d]oxazol‐2(3H)‐one), a macrophage migration inhibition factor (MIF) antagonist, used as a small molecule inhibitor of migration inhibitory factor
• 17αE2 was only tested on males, as the previous report on 17αE2 by the ITP showed that female lifespan did not benefit from treatment; the other four interventions were tested on male and female mice;
• In genetically heterogeneous mice the “non feminizing” estrogen, 17αE2, extended median male lifespan by 19% and 11% when fed at 14.4 ppm starting at 16 and 20 months respectively (data pooled across the three sites University of Michigan, the Jackson Laboratories and the University of Texas Health Sciences Center at San Antonio), confirming previous reports from the ITP;
• Although the increased lifespans of the males started on the 17αE2 diets at 16 or 20 months were not statistically different, males that started at 16 months tended to live longer, hinting that benefits from 17αE2 diminish when treatment is started at 20 rather than at 16 months.
• The consistently large lifespan benefit in males, even when the treatment is started in older mice, could provide information on sex-specific aspects of aging;
• What about the other interventions?
  • NR – total NAD+ levels decline with age in a wide range of species. Importantly, increasing NAD+ levels benefit a wide variety of tissues in species including mice and human being.
  • Candesartan cilexetil is an angiotensin-receptor blocker. When angiotensin-receptors are knocked-out in mice an increase in lifespan was observed.
  • Geranylgeranylacetone induces heat shock proteins in mammalian tissue (Hsp70) and promotes insulin sensitivity in old mice. Heat shock proteins are vital to maintain good quality protein in the body and it has been shown that long-lived species have elevated HSP levels in comparison to short-lived species within the same order.
  • MIF098 inhibits migration inhibitor factor (MIF), a proinflammatory cytokine. Inhibition of MIF may reduce chronic inflammation associated with age, as suggested by the fact that MIF-knockout mice live longer than controls.
• NR led to a marginally significant increase in female lifespan at one site, but this was balanced by a marginally significant decline in female lifespan at another (in addition to a marginally significant decline in lifespans of males at a single site). The ITP endpoint is always a pooled data set and therefore, overall, NR had no significant effect, positive or negative, in the pooled data for either sex. NR treated mice had significantly more nicotinamide in serum levels than controls. No NR was detected, perhaps due to the higher detection limit for NR than nicotinamide (500ng/ml compared to 25ng/ml) or possibly because by the time NR was in the blood it was metabolised to nicotinamide.
• In females, weights of mice fed GGA were similar to weight of controls, whilst females fed NR, CC and MIF098 were about 5g lighter than controls. In males, weights of mice fed NR, CC, GG and MIF098 were similar to control groups.

Do check out the full paper and results here, and we look forward to covering what the longevity community’s views are in the future.

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