#10 – Matt Kaeberlein, Ph.D.: rapamycin and dogs — living longer, healthier & turning back the clock

KEYPOINTS

• 01

  A seminar in his first semester steered Kaeberlein toward aging

  Trained in biochemistry and mathematics and planning a career in structural biology, Kaeberlein heard Lenny Guarente talk about the genetics of aging at MIT. His PhD work went on to show that boosting Sir2 extended lifespan in yeast. A year later, Heidi Tissenbaum showed the worm version did the same, the first conserved genetic regulator of lifespan across such distant species.

• 02

  Pet dogs are a better step toward humans than lab mice

  Lab mice are inbred and live in controlled cages. Companion dogs are genetically diverse, share our homes and get many of the same age-related diseases; cancer is their top killer, and big dogs get more of it. Kaeberlein also argues that people will believe aging can be slowed far more readily when they see it in their own dog than in a news article.

• 03

  Treating healthy individuals demands a very low tolerance for side effects

  Geroscience aims to intervene before disease, the reverse of traditional medicine, so regulators and the public accept little risk. Kaeberlein argues society should debate that standard, because a 'healthy' 70-year-old isn't the same as a healthy 30-year-old and we know what happens if aging goes untreated.

• 04

  Intermittent dosing may boost immunity rather than suppress it

  Joan Mannick's study gave healthy older people the rapamycin analog everolimus at 20 mg weekly, 5 mg weekly or 1 mg daily. All three improved their flu vaccine response, with the 5 mg weekly dose doing best with the fewest side effects, and none severe enough for anyone to drop out. Attia notes this runs counter to rapamycin's reputation as a transplant immunosuppressant.

• 05

  Short rapamycin courses partly reversed heart aging in old mice

  In three independent studies, six to ten weeks of rapamycin restored ultrasound measures of heart function in old mice about halfway to young levels, without needing a break from the drug to see the effect. Kaeberlein lists other short-term 'rejuvenation' signals: intestinal stem cells (from a colleague's lab) and the bone around the teeth (from his own). He cautions that doses don't translate cleanly between species.

• 06

  Rapamycin's cancer effects depend on dose

  Immune surveillance is a major defence against cancer, and it weakens with age. Kaeberlein guesses that moderate rapamycin delays cancer in mice by restoring immune function, while doses high enough to suppress immunity could promote it. Tumours that have already learned to ignore mTOR signals may not respond.

• 07

  A 'party dose' revealed striking sex differences

  His lab gave mice 8 mg/kg daily injections, the highest dose ever used in an aging study, for three months from 20 to 23 months of age. Males lived about 60% longer after treatment ended, with better muscle function and less cancer. Females gained no lifespan and all died with aggressive blood cancers. He speculates the dose overshot in females, who may be more sensitive to rapamycin, even though the 2009 study that started the field showed a bigger benefit in females.

• 08

  Alzheimer's should be treated as a disease of aging

  Kaeberlein believes rapamycin has a decent chance in dementia, ideally starting at mild cognitive impairment, but such trials are long and progression is hard to predict. He thinks drugs fail partly because researchers create the disease in young mice. Attia, who doesn't see Alzheimer's as one disease, is most optimistic about the metabolic form. Kaeberlein adds that rapamycin's boost to autophagy (cellular clean-up) might help the harder forms too.