All 30 milestones, in order
Oldest first. The year rail is to scale in one respect only: where the field stood still, the gap says so. 5 of the 30 were done in humans. Prefer a picture? The same studies are on the interactive timeline.
- 1975
Rapamycin isolated
Vézina, Kudelski & Sehgal · J Antibiot · 1975 · Microbial
A soil microbe from Easter Island makes a molecule that clearly slows cell growth – but nobody yet knows what it latches onto inside the cell.
- 1991
TOR1/TOR2 in yeast
Heitman, Movva & Hall · Science · 1991 · Yeast
Yeast that had become resistant to the drug pointed straight at its target genes, TOR1 and TOR2 – turning a drug into a genetic tool, and starting the whole field.
What stayed open The paper frames rapamycin as an immunosuppressant that blocks T-cell activation. That framing survives eighteen years, until it is inverted (Araki, 2009).
Builds on Rapamycin isolated made it possible
- 1994
RAFT1 – mammalian TOR
Sabatini et al. · Cell · 1994 · Mammalian cells
The same gene turns out to exist in humans too – meaning everything learned in yeast could now apply to human biology.
Builds on TOR1/TOR2 in yeast is extended here
- 1994
FRAP – parallel find
Brown, Albers … Schreiber · Nature · 1994 · Mammalian cells
A second lab finds the very same protein within weeks, using a different method – a sign this was a question the whole field was closing in on at once.
Builds on TOR1/TOR2 in yeast is extended here
- 2002
Raptor
Kim, Sarbassov … Sabatini · Cell · 2002 · Mammalian cells
mTOR isn't a lone enzyme – it works as part of a larger complex, and Raptor is the scaffold piece that lets it reach the right targets.
Builds on RAFT1 – mammalian TOR made it possible
- 2002
Raptor – parallel find
Hara, Maruki … Yonezawa · Cell · 2002 · Mammalian cells
Another lab publishes the same discovery side by side, plus evidence in a living worm that this scaffold protein matters for a whole animal, not just cells in a dish.
Builds on RAFT1 – mammalian TOR made it possible
- 2002
TORC1 vs TORC2 in yeast
Loewith … Hall · Mol Cell · 2002 · Yeast
Yeast reveals the bigger picture two years before mammals do: there are actually two separate TOR complexes, and the drug only blocks one of them.
Builds on TOR1/TOR2 in yeast is extended here
- 2003
TSC2 is a GAP for Rheb
Inoki, Li, Xu & Guan · Genes Dev · 2003 · Mammalian cells
The final piece connecting growth-factor signals to mTOR clicks into place: Akt turns off a brake (TSC), which then releases the gas pedal (Rheb) that switches mTOR on.
Builds on RAFT1 – mammalian TOR made it possible
- 2003
AMPK phosphorylates TSC2
Inoki, Zhu & Guan · Cell · 2003 · Mammalian cells
The cell's low-energy alarm (AMPK) is now wired into the same brake: when energy runs low, AMPK reinforces the brake on mTOR – the mechanistic link to calorie restriction, and later to the diabetes drug metformin.
Builds on TSC2 is a GAP for Rheb is extended here
- 2003
Lifespan+ in C. elegans
Vellai … Müller · Nature · 2003 · C. elegans
For the first time, this pathway is linked to how long an animal lives – turning it from a story about cell size into a story about ageing.
Builds on TOR1/TOR2 in yeast is extended here
- 2004
Rictor / mTORC2
Sarbassov … Sabatini · Curr Biol · 2004 · Mammalian cells
Two separate lines of research – yeast genetics and human biochemistry – arrive at the same answer at the same time: the second complex, mTORC2, really exists.
Builds on TORC1 vs TORC2 in yeast converges here Raptor converges here
- 2004
Lifespan+ in Drosophila
Kapahi, Zid … Benzer · Curr Biol · 2004 · Drosophila
The same lifespan effect shows up in a second species, and it depends on how much food the animal gets – the first strong clue that this pathway is the actual mechanism behind the benefits of calorie restriction.
Builds on Lifespan+ in C. elegans is extended here
- 2005
mTORC2 phosphorylates Akt
Sarbassov, Guertin, Ali & Sabatini · Science · 2005 · Mammalian cells
mTORC2 turns out to be the missing piece that fully switches on Akt, a major growth signal – tying the two mTOR complexes into one system that can't easily be split apart.
What stayed open The origin of the selectivity problem: chronic rapalog dosing eventually reaches mTORC2, which is where the insulin resistance and hyperlipidaemia seen in the clinic come from.
Builds on Rictor / mTORC2 made it possible
- 2005
Restriction acts via TOR
Kaeberlein … Kennedy · Science · 2005 · Yeast
Removing the TOR gene and restricting calories turn out to do the exact same thing – they don't add up, because they're really the same intervention.
Builds on TOR1/TOR2 in yeast is extended here
- 2007
Temsirolimus, phase 3
Hudes … Motzer · N Engl J Med · 2007 · Human
The first solid evidence in actual patients: a related drug helps people with advanced kidney cancer live longer, and doctors get their first clear picture of its side effects (rash, swelling, high blood sugar, high cholesterol).
What stayed open An oncology endpoint in sick patients says almost nothing about dosing a healthy person for decades.
Builds on RAFT1 – mammalian TOR made it possible
- 2008
Rags sense amino acids
Sancak … Bar-Peled, Sabatini · Science · 2008 · Mammalian cells
Amino acids turn out to switch mTOR on in an unusual way – not by directly activating it, but by moving it to a different spot inside the cell where it can then be turned on.
Builds on Raptor made it possible
- 2009
mTORC1 → ULK1: autophagy
Hosokawa … Mizushima · Mol Biol Cell · 2009 · Mammalian cells
The direct wiring between “nutrients are available” and “stop the cell's self-cleanup process” is found – the same wire connects mTOR to nearly every process linked to ageing that people care about.
What stayed open Nutrient input is dynamic, but this is measured as an on/off state. Whether the timing of mTORC1 release, rather than its average level, sets autophagic flux is unsettled.
Builds on Raptor made it possible
- 2009
Mouse lifespan +14%
Harrison, Strong … Miller · Nature · 2009 · Mouse
A drug given to mice as old as a 60-year-old human still extends their lives – about 14% in females, 9% in males – and three independent labs get the same result. The single biggest result in this whole field.
What stayed open It is a mouse. Seventeen years on, no human trial has tested a lifespan or healthspan endpoint. Everything above this node on the human side is inference.
Builds on Lifespan+ in C. elegans is extended here Lifespan+ in Drosophila is extended here Restriction acts via TOR is extended here
- 2009
Rapamycin boosts memory
Araki … Ahmed · Nature · 2009 · Mouse & primate
A drug that had been used for 18 years purely to suppress the immune system turns out to also make immune memory cells work better – flipping the field's assumption about what it does.
What stayed open Immunosuppression and immune enhancement depend on dose and timing. Nobody has mapped where that boundary sits in humans.
Builds on TOR1/TOR2 in yeast is overturned here Raptor made it possible
- 2010
mTORC1 on the lysosome
Sancak, Bar-Peled, Zoncu … Sabatini · Cell · 2010 · Mammalian cells
The lysosome – long thought of as just the cell's trash bin – turns out to be the platform where the decision to grow gets made.
Builds on Rags sense amino acids is extended here
- 2011
v-ATPase: inside-out
Zoncu, Bar-Peled, Efeyan … Sabatini · Science · 2011 · Mammalian cells
The nutrient signal starts from inside the lysosome and gets read from the outside – a surprising, inside-out way for a cell to sense its surroundings.
Builds on mTORC1 on the lysosome is extended here
- 2011
Everolimus, BOLERO-2
Baselga … Hortobagyi · N Engl J Med · 2011 · Human
Adding this drug to standard hormone therapy roughly doubles how long advanced breast cancer stays under control – the drug becomes a normal part of cancer treatment, and doctors learn its side effects in thousands of patients.
Builds on Temsirolimus, phase 3 is extended here
- 2012
4E-BPs and TOP mRNAs
Thoreen, Chantranupong … Sabatini · Nature · 2012 · Mouse cells
Blocking mTOR completely and checking exactly which genes stop being read shows the effect runs almost entirely through one protein family (4E-BPs) – overturning an earlier, more complicated model.
What stayed open Rapamycin only partially inhibits 4E-BP phosphorylation – so twenty years of rapamycin data were reading a partial inhibitor as if it were complete.
Builds on Raptor made it possible
- 2012
mTORC1 → TFEB
Settembre, Zoncu … Sabatini, Ballabio · EMBO J · 2012 · Mammalian cells
Two separate parts of the story merge into one: mTOR, sitting on the lysosome, directly controls the master switch (TFEB) that builds more lysosomes and turns on cleanup.
What stayed open TFEB shuttles in and out of the nucleus – an inherently time-dependent readout, and a natural place to test whether pulse frequency carries information.
Builds on mTORC1 on the lysosome converges here mTORC1 → ULK1: autophagy is extended here
- 2013
GATOR1 / GATOR2
Bar-Peled, Chantranupong … Sabatini · Science · 2013 · Mammalian cells
A whole new set of brake-and-release proteins for amino-acid sensing is found – some of which are mutated in human cancers, and one that later leads researchers to the actual leucine sensor.
Builds on Rags sense amino acids is extended here
- 2014
RAD001 in older adults
Mannick … Klickstein · Sci Transl Med · 2014 · Human
For the first time, the “ageing” side of this research reaches an actual human: a low dose of the drug improves older adults' response to a flu vaccine by about 20% and reduces a marker of immune exhaustion.
What stayed open The endpoint is a surrogate – antibody titre, not health, not lifespan.
Builds on Rapamycin boosts memory is extended here Mouse lifespan +14% is extended here
- 2015
Sestrin2: leucine sensor
Wolfson, Chantranupong … Sabatini · Science · 2015 · Mammalian cells
A twenty-year mystery is solved: a protein is found that grabs onto leucine directly, at just the concentration where leucine is known to switch mTOR on. The cell really does have a dedicated leucine detector.
Builds on GATOR1 / GATOR2 made it possible
- 2016
RapaLink-1
Rodrik-Outmezguine … Rosen, Shokat · Nature · 2016 · Cells & mouse
Chemists link two separate drug parts into a single molecule that gets around the resistance mutations that beat both earlier generations of the drug – the chemistry that first makes a much more selective mTOR-blocker seem possible, and the direct ancestor of the newer drugs now in human trials.
What stayed open Selectivity in cells is not selectivity in a person dosed for years.
Builds on mTORC2 phosphorylates Akt made it possible Temsirolimus, phase 3 is overturned here
- 2018
Phase 2a: fewer infections
Mannick … Klickstein · Sci Transl Med · 2018 · Human
264 older adults took a low dose for six weeks, and over the following year they reported significantly fewer infections – the strongest positive human signal this field has produced so far.
What stayed open Phase 2a, self-reported infections. Closer to health than a titre – but still not ageing.
Builds on RAD001 in older adults is extended here
- 2021
Phase 3 misses endpoint
Mannick … Shergill · Lancet Healthy Longev · 2021 · Human
In a trial of over 1,000 people, the drug switched on the right antiviral genes just like before – but it did not actually reduce how many people got sick with respiratory illness (26% vs. 25%, essentially no difference).
What stayed open The biomarker moved and the patient did not. This is the node most databases would quietly omit, and the reason the Atlas records failures at the same weight as successes.
Builds on Phase 2a: fewer infections is overturned here
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