Aging rate indicators and the search for anti-aging drugs

Austad SN, Kaeberlein M, Miller RA

1. 01

   Synthesizes NIA ITP data: 14 agents now shown to extend mouse lifespan in standardized testing, often when started in late adulthood

2. 02

   Proposes 12 candidate aging rate indicators (ARIs) spanning adipose UCP1, cap-independent translation, MEK/ERK and MEK/p38 signaling, mTORC1 activity, adipose macrophage M1/M2 ratio, FNDC5, GPLD1, and hippocampal BDNF/doublecortin

3. 03

   Goal: a biochemical panel readable in months, versus 2-3 years for a full mouse lifespan study, to accelerate geroprotector screening

4. 04

   Rapamycin is explicitly flagged as not fitting the UCP1 pattern seen with other ITP-validated agents

5. 05

   Sex-specific responses were common: 9 of 14 lifespan-extending agents benefited only males in the underlying ITP data

6. 06

   No ARI has yet been validated in any species other than mice; authors call for replication across other mouse colonies, then dogs, non-human primates and humans

Study Design

Review

Sample Size

Not reported

Study Duration

Not reported

Methodology

Narrative synthesis and proposal paper drawing on published NIA Interventions Testing Program lifespan data and associated mechanistic/metabolomic studies across 14 agents; no new primary lifespan data generated.

Limitations

Perspective/synthesis, not new experimental data. The great majority of underlying ARI data come from a single laboratory group using a single mouse stock; replication in other colonies is needed. Most ARI measurements were taken at one timepoint (drug start 4 months, readout 12 months), so the time-course of each indicator is unclear, and some ARIs themselves decline with age independent of treatment. Sex-specific effects were common and not fully explained. No ARI has been validated in humans, non-human primates, or dogs; the proposed TAME human trial that would test a related concept remains unfunded. Not a validated biomarker panel and nothing in it is clinically measurable today.