The Interventions Testing Program (ITP) at the National Institute on Aging runs very rigorous, costly life span studies in large numbers of mice, picking a few interventions to test each year. The usual outcome is that a treatment with some interesting past results is found to have absolutely no effect on life span when run through the rigor of the ITP process. We should all bear this in mind whenever modest life span extension in mice is reported by researchers elsewhere in the community. Based on past ITP data, a great many such results are the result of chance or poor experimental design.
Will the ITP ever get around to testing senolytics or other potential rejuvenation therapies? They are dosing a group with fisetin, but overall their bias is towards approved drugs and existing supplements, calorie restriction mimetics, and similar classes of intervention that affect metabolism in well-explored ways: insulin signaling; blood pressure; inflammation; and so forth. Senolytics are likely not yet a well trodden enough path for most to get past the selection process.
Today's open access paper reports the latest set of interventions to have shown minimal, gender specific, or no effects at all on mouse life span in the ITP process. Of interest to the community here, nicotinamide riboside supplementation is one of these, and does not extend mouse life span. We might compare that outcome to the 2016 paper in which mouse life span does increase modestly, the human trial in which benefits to cardiovascular function result, and all of the other data showing improved stem cell and tissue function in mice and humans.
We might view the ITP as a steamroller encouraging us to run faster, to aim higher, to stop messing around with approaches to aging that do not and cannot have large enough effects to matter at the end of the day. The only goal worth aiming for is robust, sizable rejuvenation of the old. We have excellent starting points in the form of the SENS proposals for repair of cell and tissue damage, and the existence of the senolytics industry indicates just how fast things can move once impressive data is produced in animal studies. More of that sort of thing is much needed if we are to realize the promise of modern biotechnology.
The interventions for the present study were chosen for the following reasons:
(a) 17-α-estradiol (17aE2) is a relatively "non-feminizing" estrogen which shows reduced activation of classical estrogen receptors compared with 17-β-estradiol. It was reported that in UM-HET3 mice fed 4.8 mg 17aE2/kg (4.8 ppm) diet from 10 months of age, median male lifespans increased 12%, while 17aE2 did not alter female lifespan. Other researchers showed that using a threefold higher dose (14.4 ppm) from 10 months of age, pooled median male lifespans increased 19%; the 90% lifespan increased 12%, but females still did not benefit. Thus, only males were tested in the present study. To determine whether 17aE2 treatment is effective when initiated in older mice, males were treated beginning at 16 or 20 months of age, choosing middle age, and early old age before many natural deaths.
(b) Nicotinamide riboside (NR) is a precursor of nicotinamide adenine dinucleotide (NAD) via the cell's salvage pathway. 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 beings. it has been suggested that NAD+ boosters may "..delay aging and age-related physical decline." It was reported that NR delays senescence of neural stem cells (SCs) and melanocyte SCs and increases mouse life span, even when given in old age (5% increase at 20 months of age).
It was reported that in mice and humans NR is bioactive when given by mouth, unlike most other nicotinamide derivatives. In a 2016 study NR improved liver function and protected against diabetic neuropathy. When fed to C57BL/6 J mice from 10 weeks of age, NR protects against high-fat diet (HFD)-induced obesity and promotes oxidative metabolism by increasing the NAD+/NADH ratio in muscle, liver, and brown adipose tissue. Researchers found that increasing NAD+ stores with NR supplementation improved muscle function and alleviated heart defects in a mouse model of muscular dystrophy. It was reported that an NR metabolite, nicotinamide, did not increase lifespan when started at 12 months in C57BL/6 J mice but improved some health outcome measures. Due to its benefits in a variety of diseases, and reports of benefits in mouse lifespans, NR treatment was proposed to increase lifespan in UM-HET3 mice.
c) Candesartan cilexetil (CC) is an angiotensin-receptor blocker, which lowers blood pressure and improves cardiovascular function and insulin sensitivity in obese, hypertensive patients. Importantly, angiotensin-receptor knockout increases lifespan of mice. Because CC is effective against age-related diseases, and sensitizes the body to insulin, and because the angiotensin-receptor knockout increases lifespan of mice, treatment with CC was hypothesized to increase lifespan.
(d) To maintain good quality protein in the body, heat shock proteins (HSPs) are vital. Geranylgeranylacetone (GGA) induces heat shock protein (Hsp70) in mammalian tissues and promotes insulin sensitivity in old mice, while it increases HSP expression in atrial tissue after heart surgery. Long-lived species, compared with related short-lived species within the same order, have elevated HSP levels in conjunction with better proteostasis. To test whether treatment with an established HSP inducer can increase lifespan in a mammalian model, UM-HET3 mice were treated with GGA.
(e) MIF098 ((3-(3-hydroxybenzyl)-5-methylbenzo[d]oxazol-2(3H)-one) is a macrophage migration inhibition factor (MIF) antagonist that regulates CD44 binding. MIF is a proinflammatory cytokine, so MIF098 reduces inflammation. This may include the chronic inflammation that increases with age, as suggested by the finding that MIF-knockout mice live significantly longer than controls. Because it is orally bioavailable and shows MIF inhibitory activity in mouse models of hyperoxic lung injury, as well as in other diseases, treatment with MIF098 was proposed to increase lifespan by decreasing chronic inflammation and disease.
Our new data show that nicotinamide riboside (NR) failed to increase lifespan. Only 17aE2 increased lifespan, and benefits in males occurred even when the drug was not fed until late middle or early old age (16 and 20 months of age, respectively). The range of ages for which treatment is effective suggests that benefits from 17aE2 do not depend on effects earlier in life, such as growth alteration. Interventions that are effective when started at a late age have considerable translational potential.