Longevity FAQ

A beginner's guide to longevity research

Longevity FAQ: A beginner's guide to longevity research

 

Hi! I'm Laura Deming, and I run Longevity Fund. I spend a lot of time thinking about what could increase healthy human lifespan. This is my overview of the field for beginners. Feel free to send me any questions  about the below (just include name and affiliation).

 

Overview:

Introduction

As you get older, the chance that you will die goes up.

 

My Ideas - 2-2.png

 

As you get older, the chance that you will die from certain diseases also goes up. 

My Ideas - 7-2.png

Why does this happen? 

 

A simple explanation would be that, like an old car, you accumulate damage in a random fashion. 

 

However, there are many simple things that we can do to make animals live longer. Why? We don’t really know.

 

Eating less makes mice live longer.

 

My Ideas - 4-2.png

 

Some genes, when mutated, make mice live longer,

My Ideas - 5-2.png

 

A few drugs, approved for human use, also make mice live longer.

My Ideas - 6-2.png

There are others - we will cover them below. 

 

So what is the study of aging?

 

I sum it up as the following: trying to figure out what kinds of damage accumulate with age, how to reverse that accumulation, and the search for switches that we could flip in human biology to increase lifespan.

 

 

Research areas in longevity

Caloric Restriction

 

at a glance: eating less, in a variety of ways, can make you live longer - but is your body just using number of calories as a signal?

 

In the 1930s, investigators wanted to do an experiment to see if stunted growth rates during the Great Depression might impact lifespan. They tested this in rats by feeding them less food than they would normally eat. To their surprise, this actually made the rats live longer! This was a seminal discovery. For the first time, we changed the environment of an animal to make it live longer than it normally would. 

 

Since then, investigators have tried to uncover how this works. The effect depends on what genes you have, what you are eating and how much less you eat. If you take many genetically distinct mouse strains and put them on the same diet (cutting calories by ~40%), sometimes fewer than 1/5 of the mouse strains live longer. Diet composition also plays a role. Just decreasing protein or a specific amino acid, while keeping total calorie intake the same, can result in a lifespan extension in mice. Feeding mice a ketogenic diet also seems to help. Decreasing food intake by too much will result in starvation, so finding a diet that works can depend on the situation.

 

While long-term human studies are sparse, investigators have run two caloric restriction experiments in monkeys, one of which showed promising results for an increase in survival. To avoid the difficulty of continuous dieting, fasting ~8+ hours a day, or 5 days/month, or on a variety of different cycles might also be helpful. This is called intermittent fasting. Medically, intermittent fasting may aid recovery during chemotherapy. Some longevity-related pathways involve sensing amino acid levels, so it is possible that a specific biological process, not total calorie intake, controls the increase in lifespan.

 

Insulin/IGF

 

at glance: genetic pathways related to growth and insulin signaling are linked to aging

 

In papers published in 1983-1993, investigators introduced the concept that a gene could control lifespan. I got my start in science when one of the founders of this field, Cynthia Kenyon, agreed to let me work in her lab as a 12 year old kid. I'll always be grateful for her kindness and mentorship. Previously we'd known that caloric restriction could make animals live longer, but Kenyon and other scientists including Michael KlassDavid Friedman and Tom Johnson found mutant genes that could make worms live longer. The gene that Kenyon found encoded a protein that is similar to insulin-like growth factor and insulin receptors in humans. In mice, mutating members of both of those pathways can increase lifespan. One of the longest-lived mouse mutants we have today is a dwarf mouse. In one study, people with similar dwarf mutations seemed to suffer less age-related disease than their non-mutated relatives.

 

I'm fascinated by the fact that many drugs which have been developed for diabetes, without any thought for their use elsewhere, turn out later to be relevant to aging. Good examples of this are metformin and FGF-21. Metformin is a small molecule used to treat Type 2 Diabetes, and FGF-21 is a protein in your blood that can increase lifespan in mice. We are still figuring out how the insulin/IGF pathway works, in particular what kinds of molecules might be driving the lifespan effect that we observe. 

 

Parabiosis

 

at a glance: young blood makes old mice healthier, but why?

 

Dracula wanted to drink young blood, but what does that have to do with aging? A paper published in the 70's showed that linking old and young female mice so that they share a bloodstream increased lifespan. Decades later, in 2005, scientists at Stanford showed that this procedure might help old muscle stem cells repair wounds. Then, in 2011, a succession of papers came out showing that this procedure and others like it (such as injecting young blood into old mice) made mice better at remembering things, and improved heart and muscle function with age. These discoveries increased excitement and interest in the field, and lead to a wave of startups. 

 

Investigators in the field have proposed many possible causes for this phenomenon. Proteins, small vesicles, or cells in the young mouse cleaning the blood of the old mouse might all be part of the effect. Many companies are trying to figure out whether there is a special protein or molecule involved. The big questions to resolve will be whether we can isolate a few key factors that are responsible for the parabiosis effect, and how many of the longevity-related phenotypes will translate to improve human health.

 

Senescence

 

at a glance: a fraction of your cells get older than the others, so we'd like to eliminate them

 

As you get old, so do your cells. But some of your cells get old in a way that is much worse than the others. You may have heard of a thing called telomerase. If you remember correctly, it's the thing that keeps the end of your DNA long enough that your cells can still divide. When one of your cells runs out of telomerase, it can't make many more copies of itself. If the cell sticks around, refuses to die even when it stops working, and starts secreting signals to the immune system, we call that a 'senescent cell'.

 

What happens when you get rid of these cells? Some animals that age faster than normal have a lot of these 'senescent cells' and are good experimental models in which to ask that question. In 2011, a group from the Mayo Clinic cleared out many of the senescent cells in one of those animal models, and found that the resulting mice were healthier in old age (among other things, they did not get cataracts and bent spines, which typically emerge in old age). In 2016, the same investigators found that getting rid of senescent cells in normal mice made them live a longer healthy lifespan. Knocking out senescent cells is tricky, because they don't have many unique identifiers. Companies are working to either find things empirically that kill senescent cells, or figure out specific mechanisms by which to try to destroy them.

 

Autophagy

 

at a glance: the garbage disposal unit of the cell worsens with age, improving it might increase healthy lifespan

 

Your body makes a lot of junk, on the molecular level, and cells need to clean this up. Just increasing the expression of one protein that helps to clean up this junk was enough to make mice live ~17% longer. Cells recycle old proteins and other molecules into a big vesicle, called a lysosome. It contains many proteins, and their job is to chop up old cell parts that it engulfs. Genes for proteins that do work in the lysosome are mutated in diseases such as Parkinson's. So improving this process has immediate relevance to neurodegenerative disease. As the lysosome gets older, more junk builds up in it that it cannot degrade. Finding ways to make more lysosomes, or help lysosomes degrade junk, may be interesting therapeutic avenues to pursue. 

 

Hypothalamus

 

at a glance: a surprising number of things can increase lifespan when only changed in the brain tissue

 

Changing something just in the brain can be enough to make a mouse live longer. If the hypothalamus thinks it is too warm, for example, it can decrease the core body temperature of a mouse, resulting in a slightly longer lifespan. Changing the level of a variety of genes in a brain-specific way can also make a mouse live longer.We know that the hypothalamus makes something called growth hormone releasing hormone (GHRH), which is in charge of, well, releasing growth hormone. Growth hormone appears to be closely tied to lifespan, so the hypothalamus could be an important control point. One interesting question is how much you can affect the lifespan of a whole organism by just making changes to the brain.

 

Reproductive System

 

at a glance: removing the ability to reproduce can increase lifespan

 

10 years ago, one of the first projects I worked on was trying to understand a weird fact about reproduction in worms. If you take little worms and get rid of their gonads (I know, it's weird), they live ~60% longer than normal. But this only works if you get rid of the stuff inside (sperm/eggs - these worms are hermaphrodites, which means they carry around both). If you get rid of the whole thing, lifespan goes back to normal.

 

This isn't restricted to worms. From court records of Korean eunuchs, the eunuchs tend to live longer than their contemporaries by 14-19 years. Some people have tried to do things such as transplant young ovaries into old mice, to see if that helps (it might add a bit to lifespan). There are also many reports showing that when you make things live longer, fertility goes down. There might be a tradeoff (fertility takes away resources that could be used for something else), or a signal coming from the reproductive system that tries to hold up aging if it is damaged.

 

Mitochondria

 

at a glance: mitochondrial mutations impact lifespan in counterintuitive ways

 

You may have heard mitochondria referred to as the 'powerhouses' of the cell. It's funny, they do literally run like a dam generating hydroelectric power! - They pump protons (positively charged particles) one way, then use them as they slide back to run a kind of motor that makes a small energetic molecule used by many entities in the cell. One concept that comes up when people talk about mitochondria is 'oxidative stress' - the idea that if molecules are very reactive (say they have oxygen, acquire some extra electrons, and now want to discharge them onto other molecules), they are likely to interfere with a lot of other molecules in the cell that should be left to their own devices.

 

Weirdly, the story has turned on its head over time. It's true that it is bad to pump an animal full of reactive oxygen species, and that you can make a mouse live longer by increasing the level of proteins that are supposed to clean up mitochondria. But you can also mutate things that should be helping the mitochondria, and end up increasing lifespan! It's counterintuitive, and one hypothesis is that a little bit of stress is good because it forces your cells to put up their defenses and ramp up production of molecules that neuter the reactive oxygen species. But we don't really know. 

 

Sirtuins

 

at a glance: sirtuins can change DNA and increase lifespan

 

Sirtuins add tags to the structural protein balls that DNA wraps around. It sounds odd, but think of yarn wrapping around a cardboard tube. When they add tags to the DNA yarn ball, it changes how the DNA is folded and expressed. So one of their actions is to control what genes do.

 

Sirtuins were first discovered to increase lifespan in yeast, and seem to also do so in worms, flies and mice. They depend on NAD to do their job, so when you see people talking about NR or other precursors of NAD, you can think about them as also helping the sirtuins do their job. You can extend lifespan a little bit in mice by giving them NR in old age. 

 

[That's all for this part for now - I'm planning to add to the above, as time allows. There's lots more to talk about!]

 

Data on longevity

To give some context for the field, I thought it would be fun to do a more comprehensive survey. Below are virtually all the things we've seen that might improve mouse lifespan, listed in order of citations/year. 

 

I think some of the papers on the bottom of the list are actually pretty cool and might have been given a short shrift

 

(Methodology - I took all papers that had a demonstrated mouse lifespan effect, extracted the key lifespan figure, and in cases where the text didn't list actual median or other lifespan used a virtual pixel ruler to count the pixels to the median point. Allow for some standard deviation of error accordingly!).

95 things that make mice live longer Ordered by citations/year
Intervention Median lifespan increase (treated/control) Year Published Notes Reference
Senescent cell removal 135% 2016 Does not affect rotarod performance, object discrimination. Slight delay in wound closure. 1
Rapamycin 110% 2009 Late-life rapamyicn treatment extends lifespan (pooled females from multiple-site NIA study) 2
NR 105% 2016 Claim an increase in running distance 3
Catalase 117% 2005 Mitochondrially-targeted catalase expression extended mouse lifespan compared to control 4
Sirt6 overexpression 115% 2012 Sirt6-overexpression increases male mouse lifespan 5
Metformin 106% 2013 In males, small but significant lifespan extension after metformin application 6
DN-IκBα 110% 2013 Dominant negative to downregulate IKK-beta activity, delivered to hypothalamus of middle-aged mice 7
Klotho 120% 2005 Overexpression under human elongation factor 1α promoter increases lifespan, slight fertility loss 8
S6K1 118% 2009 KO of S6K1 extends lifspan compared to wildtype mice 9
p66 128% 1999 Mutation of a p66shc, member of proto-oncogene locus SHC, extends lifespan. May be just due to cancer effect. 10
Lowering protein:carbohydrate ratio 128% 2014 Varied protein, carbohydrate, and total energy levels. 11
Fat-specific insulin receptor knockout mice 111% 2003 Fat-specific insulin receptor knockout mice show a significant increase in lifespan 12
C57BL/6 mice with NZB/OlaHsd mitochondrial mutations 120% 2016 Same nuclear, different mitochondrial DNA. 13
Fasting mimicking diet 112% 2015 FMD followed by 10 days of normal, then repeat 14
Rapamycin 127% 2014 Rapamycin from 9 months of age, weight decreased ~30% at highest dose 15
Brain-specific Sirt1 expression 116% 2013 Brain-specific Sirt1 expression in female mice increases lifespan over wildtype 16
SRT1720 104% 2014 Start diet at 28 weeks of age, very small increase on lifespan 17
Spermidine 111% 2016 Polyamine, administered in drinking water 18
Atg5 overexpression 117% 2013 Transgenic mice ubiquitously expressing Atg5 (crucial for autophagasome confirmation) live longer. 19
Telomerase 124% 2012 Paper showing telomerase therapy increasing life 20
Insulin receptor substrate null 132% 2008 Insulin receptor substrate 1 null mouse lifespan extension in females 21
Snell Dwarf Mice 142% 2001 Snell dwarf mouse paper showing life extension 22
Ames Dwarf Mice 168% 1996 Original Ames dwarf mouse paper showing life extension 23
s-Arf/p53 113% 2007 An extra copy of p53 and upstream regulator Arf/p16Ink4a increases lifespan 24
Slow growth during lactation 106% 2004 Male mice suckled by dams fed a low-protein diet lived longer than their control cohort 25
Methionine restriction 111% 2005 Methionine restriction increases mouse lifespan, here median lifespan increase in mice that survived at least 1 yr. 26
Rapamycin (3 months) 114% 2016 Lifespan given from time of treatment which was 23-24 mo, used 24 mo to get percentage so this is an estimate 27
GHR-BP 138% 2000 Mice deficient in growth hormone receptor / binding protein live longer (female mean, not median, lifespan shown here) 28
mTOR 116% 2013 mTOR depletion extends lifespan 29
PTEN overexpression 112% 2012 Overexpression of PTEN, a tumor suppressor which counteracts PI3K, extends mouse lifespan 30
Myc (+/-) 121% 2015 Claim no correlation between weight and lifespan 31
FGF-21 139% 2012 Hepatic-specific expression of FGF-21 (which suppresses growth hormone and reduces the production of IGF) increases lifespan, female lifespan shown here 32
BubR1 overexpression 114% 2012 Kinase which localizes to kinetochore, overexpression increases lifespan 33
AC5 KO 132% 2007 AC5 knockount mice lived longer than control, potentially linked to effects on cAMP production and beta-adrenergic receptor signaling. 34
17-alpha-estradiol 112% 2013 17-alpha-estradiol extended lifespan in males, but not females (as expected) 35
Acarbose 122% 2013 Acarbose extended male more than female lifespan 36
TRPV1 -/- 114% 2014 Resting exchange ratio similar at 16 mo to 3 mo 37
SRT2104 106% 2014 Start diet at 28 weeks of age, very small increase if there 38
Hcrt-UCP2 128% 2006 UCP2 under hypocretin promoter lowers core body temp, increases lifespan 39
G6PD overexpression 114% 2016 Reduces NADP+ 40
IGF-1 Receptor Brain KO (+/-) 109% 2008 Brain-specific IGF-1 Receptor +/- mice live longer than WT 41
SURF-1 KO 121% 2007 Mutations in SURF1, a cytochrome c oxidase assembly factor, extend lifespan. Mitochondrial. 42
Litter enlargemnet (CR) 118% 2009 50% enlargement of litter in first 20 days, to induce caloric restriction 43
mclk-1 heterozygous 115% 2005 A heterozygous knockout of mclk1 (important in mitochondrial respiration) results in mouse lifespan extension compared to wildtype 44
Nordihydroguairaitic acid 112% 2008 NDGA and aspirin extend lifespan by a little bit. Small molecule. 45
Aspirin 108% 2008 NDGA and aspirin extend lifespan by a little bit. Small molecule. 46
SOD mimetic carboxyfullerene 115% 2008 Carboxyfullerene, described as an SOD mimetic, increased the lifespan of treated mice compared to wildtype control 47
Removal of visceral fat tissue 108% 2008 Removal of visceral fat tissue increases lifespan over control 48
Low glycotoxin diet 112% 2007 Low glycotoxin (low levels of AGE's) shown to extend lifespan 49
Per2 (-/-) 118% 2016 Lifespan study incomplete 50
Neonatal metformin 120% 2015 Animals recieved on 3, 5, 7th day after birth - bad for females, good for males. 51
GHRH KO 146% 2013 GHRH (Growth-Hormone Releasing Hormone) disruption extends lifespan, presumably through the insulin/IGF pathway axis 52
Sod-2 overexpresion 104% 2007 Overexpression of SOD-2 targeted to the mitochondrion increases mouse lifespan relative to wildtype 53
Metallothionein cardiac-specific expression 114% 2006 Cardiac-specific expression of antioxidant metallothionein extended the lifespan of wildtype mice compared to WT FVB control. 54
IGF1R(+/-) 121% 2013 Tyrosine kinase receptor activated by IGF1/2 55
Ink4a/Arf/Ink4b 116% 2009 Encodes 2 CDKs (p16 and p15), and Arf (upstream of p53) 56
Adult-onset Ghr (-/-) 100% 2016 Male mice have >2x higher insulin than female mice 57
Ovary Transplantation 117% 2003 Original paper showing that transplantation of young ovaries into old animals could result in lifespan increase 58
UCP-1 transgenic 111% 2007 Transgenic mice with skeletal muscle-specific UCP1 had increased longevity. Small increase if there. 59
PAPP 131% 2010 Knockout of PAPP-A (which enhances IGF-1 activity by degrading the inhibitory IGF-binding protein) increases lifespan over wildtype, female lifespan shown here 60
CR diet with lard 132% 2015 40% decrease starting at 4 months 61
loss of function of Riib (PKA subunit) 114% 2009 Knockout of RIIbeta, a subunit of PKA, increased lifespan in mice compared to wildtype 62
Myostatin (+/-) 109% 2015 Knockout induces double-muscle mice 63
Akt1 +/- 113% 2013 Haploinsufficiency of Akt1 increases mouse lifespan relative to wildtype. Insulin/IGF-1 pathway. 64
miR-17 117% 2014 Not clear if there is a main function for miR-17 65
NDGA 111% 2015 Makes up ~12.5% of the dry weight of leaves 66
FAT10ko 119% 2014 Ubiquitin-like protein which can signal for protein to go to proteasome. 67
Intranasal Hsp70 116% 2015 Seemed to extend lifespan when started at 17 months 68
RasGRF1(-/-) 120% 2011 Ras-guanine nucleotide exchange factor (Ras-GRF1) -/- mice displayed increased lifespan compared to wildtype. 69
Lmna-Lcs (Lamin C alone) 113% 2014 Body weight and tumor incidence increase in mice expressing only Lamin-C 70
Cisd2 overexpression 119% 2011 Cisd2 transgenic mice (expressing more of it) lived longer than wildtype. Cisd2 is a transmembrane protein expressed on the mitochondrial outer membrane and associated with a human longevity locus. 71
metoprolol 110% 2013 Administration of the beta-adrenerginc receptor blocker metoprolol to mice increased lifespan compared to wildtype 72
nebivolol 106% 2013 Administration of the beta-adrenerginc receptor blocker nebivolol to mice increased lifespan compared to wildtype 73
uPA (in ocular lens/CNS nerve cells) 118% 1997 uPA expression under alpha-crystallin promoter increases lifespan, small/eat less 74
MIF-1 KO 116% 2010 MIF-1 knockout mutant (T-cell derived cytokine) extends lifespan 75
mGsta4-null 113% 2009 Enzyme protects against lipid peroxidation, weird that less of its activity might increase lifespan 76
Muscle-specific GHRKO 109% 2015 Knockout under muscle creatinine kinase promoter 77
CAM-α(1A)AR mice 110% 2011 Mice with a constitutively active mutant form of the alpha1-adrenergic receptor (CAM-alpha1aAR) lived longer than wildtype control 78
Cardiac-specific catalase overexpression 113% 2007 Overexpression of catalase specifically in the heart in mice 79
Icariin 108% 2015 Flavonoid 80
miR-29 brain-specific KO 112% 2016 miR-29 highly expresed in brain during development 81
Bi-maternal mice 128% 2010 Mice prepared to be bi-maternal were found longer-lived than their normal cohort 82
RNase-L(-/-) 127% 2007 Knockout of RNase-L, which accelerates cell senescence when expressed, increases lifespan in mice compared to wildtype 83
hMTH1-Tg 116% 2013 Express high levels of hMTH1 hydrolase, thought to degrade 8-oxodGTP and 8-oxoGTP. Oxidative stress. 84
DGAT-1 -/- 126% 2012 Knockout of DGAT1, which catalyzes triglyceride synthesis, extends mouse lifespan relative to wildtype 85
IGFBP-2 overexpression 105% 2016 Proteins bind IGF1/2, degraded during pregnancy, delay in sexual maturity 86
PAPP-A on high-fat diet 105% 2015 Males chosen so no adverse developmental effect on fat depots 87
clk-1(-/-) with clk-1 transgene 128% 2014 clk-1 functions in ubiquinone synthesis, but levels weren't very affected. 88
AgRP -/- 110% 2006 Neuropeptide that is appetite stimulator, overexpression leads to hyperphagia and obesity. 89
Bone marrow transplantation 106% 2013 Bone marrow transplantation from young to old mice was claimed to extend lifespan 90
Young blood injections 94% 2014 Resulted in decreased lifespan 91
Nas(-/-) mice 125% 2011 Hyposulfatemic NaS1 null mice (Nas1 -/-) had an increased lifespan compared to wildtype control. 92
Cyclophilin D (+/-) 119% 2017 Decrease in maximum lifespan 93
PAPP-A in adults 120% 2017 Tamoxifen-induced knockdown 94
Mtbp (+/-) 120% 2016 Rotarod, open field, blood glucose, insulin, IGF-1 were the same. 95
SOURCE: See References for Table 1

 

 

For fun, I then took the list and matched the entries to drugs in the clinic. Part of the below might be outdated (companies sometimes take a long time to update on trial progress), but it's an interesting representation of the number of things in play that have a non-zero chance of having some impact on lifespan (would guess it to be pretty small in almost all cases though). Methodology is similar - just used clinicaltrials.gov to try to hunt down relevant trials and molecules, or googling generally. 

70 drugs in the clinic that might make people live longer Ordered by mechanism of action
Longevity class Drug Phase Developed For Developer Ref.
Insulin/IGF
Growth Hormone Receptor Antagonist
Pegvisomant (Somavert) Approved (March 2003) Acromegaly (normalizing IGF-1 levels) Pfizer 1
Akt1 antagonist
Archexin (Akt1 antisense) Phase 2 Pancreatic/Renal Cancer Rexahn Pharmaceuticals 2
PAPP-A
PAPP-A antibodies published Preclinical - 3
Insulin Receptor Antagonist
S961 and S661 Preclinical / Not Developed - 4
IGF-1 Receptor antagonists
AMG-479 (Ganitumab) Phase 2 Pancreatic cancer Amgen 5
AVE1642 Phase 2 (terminated) Liver and breast cancer Sanofi-Aventis / ImmunoGen 6
Cixutumumab Phase 2 Cancer Lilly/ImClone) 7
Linsitinib Phase 2 Ovarian Cancer OSI Pharmaceuticals / Astellas 8
AXL-1717 Phase 2 Cancer Axelar) 9
Figitumumab Phase 3 (terminated) NSCLC Pfizer 10
PL-225b Phase 1 (suspended) Cancer Piramal Enterprises Ltd / Merck 11
BIIB022 Phase 1 (discontinued) Cancer Biogen Idec 12
RG1507 Phase 2 (discontinued) Cancer Genmab / Roche) 13
Dalotuzumab Phase 2 Cancer Merck 14
NT219 Preclinical - TryNovo 15
GHRH Antagonist
JV-1-36 Preclinical - 16
JMR-132, MZ-5-156, MIA-601, MIA-479 Preclinical - 17
Somatostatin analogues
Octreotide Approved Acromegaly and certain cancers Novartis 18
Pasireotide Approved Cushing's disease Novartis 19
Sandostatin Approved Acromegaly and certain cancers Novartis 20
Caloric Restriction
Methionine-free diet
Methionine-restriction diet Phase 2 Metabolic Syndrome 21
Caloric Restriction Regimens
Caloric restriction - Age-related diseases 22
TOR
mTORC1 Inhibitors
Sirolimus Approved Organ transplantation Pfizer 23
Temisirolimus Approved Advanced renal cell carcinoma Pfizer 24
Everolimus Approved Advanced renal cell carcinoma, SEGA associated with TS Novartis 25
Ridaforolimus NDA Rejected Metastatic soft tissue or bone sarcoma Merck and ARIAD) 26
S6K1 Inhibitors
PF-4708671 Preclinical - 27
Sirtuins
Sirt1 Agonists
SRT2104 Phase 2 Diabetes, psoriasis GSK/Sirtris 28
SRT2739 Phase 1 Endotoxin-induced inflammation GSK/Sirtris 29
Available Therapeutics Shown to Extend Mouse Lifespan with No Oustanding Mechanistic Hypotheses
NDGA Phase 2 Prostate cancer 30
Aspirin (generic) Approved Vascular indications, reascularization procedures, and rheumatological disease indications 31
Metformin (generic) Approved Type II diabetes 32
17-alpha-estradiol (generic) Marketed Hair Loss
Acarbose Approved Type II diabetes 33
Telomeres
TA-65 Marketed supplement - Sierra Sciences 34
NFkB Inhibitors
IKK-beta inhibitors
Compound A Preclinical - 35
Compound 1 Preclinical - 36
NFkB Inhibitors
CAT-1004 Phase 1/2 DMD Catabasis 37
19 known drugs found to inhibit NFkB signaling Preclinical work - 38
FGF-21 Analogues
LY2405319 Phase 1 Type II Diabetes Lilly 39
BMS-986036 Phase 2 Type II Diabetes, NASH BMS 40
Ovary transplantation
Ovarian cortex transplantation n/a Improving later-life fertility 41
Surgical removal of visceral fat tissue
Surgical removal of visceral fat tissue Phase 2/3 Insulin resistance, obesity, metabolic syndrome 42
Mitochondrial manipulation
NAD+ Precursors NAD+ Precursors
Nicotinamide Marketed supplement - 43
Nicotinamide Riboside (NIAGEN) Marketed supplement - Chromadex 44
Nicotinamide Riboside/pterostilbene Marketed supplement Acute kidney injury Elysium 45
Lysosome Function Improvement
Lysosome Modulators
AT3375 Preclinical Parkinson's Amicus Therapeutics 46
PBT2 Phase 2 Alzheimer's and Huntington's Prana Biotechnology 47
Lysosomal Therapeutics Preclinical - 48
AC5 Inhibition
SQ22,536 [9-(tetra-hydro-2-furanyl)-9H-purin-6-amine],vidarabine (9-β-D-arabinosyladenine) and NKY80 Preclinical - 49
DGAT1 Inhibition
PF-04620110 Phase 1 Type II Diabetes Pfizer 50
PKA Inhibitor
H89, KT5720, PKI analogues Preclinical - 51
Low glycotoxin diet
Low-AGE diet
Low-AGE diet Phase 2 Metabolic Syndrome 52
AGE-Breakers
Alagebrium Phase 2 (terminated) Chronic Heart Failure Synvista Therapeutics 53
Benfotiamine Phase 4 Diabetic Nephropathy 54
MIF-1 Inhibition
MIF-1 Program Preclinical - Carolus Therapeutics 55
ISO-1 Preclinical - 56
alpha1-adrenergic receptor agonist
Midodrinre Approved Orthostatic Hypotension Shire 57
Plasminogen activators
Urokinase
Kinlytic Approved (in the process of returning to market) Pulmonary embolism, removing blood clots from intraveous catheters Microbix 58
PAI-1 inhibitors
TM5614 Phase 2 CP-CML Renascience 59
p53
p53 gene therapy
p53 gene therapy Approved (China) HNSCC SiBiono GeneTech 60
p53 agonists
APR-246 Phase 2 Ovarian cancer Aprea Therapeutics 61
MDM2 antagonist
idasanutlin Phase 3 AML Roche 62
AgRP Inhibition
TTP435 Phase 2 (discontinued) Obesity vTv Therapeutics 63
TRPV1 inhibition
ALD403 (anti-CGRP mAb) Phase 3 Chronic migraine Alder 64
LY2951742 (anti-CGRP mAb) Phase 3 Chronic migraine Lilly 65
AMG334 (anti-CGRP receptor mAb) Phase 3 Chronic migraine Amgen 66
TEV48125 (anti-CGRP mAb) Phase 3 Chronic migraine Teva 67
Myostatin inhibition
PF-06252616 (anti-myostatin mAb) Phase 2 DMD Pfizer 68
BMS-986089 (anti-myostatin mAb) Phase 3 DMD BMS 69
Cyclophilin D inhibition
CC-1233 Preclinical Acute pancreatitis, neurodegeneration Cypralis 70
SOURCE: See References for Table 2

 

Thanks to Patrick Collison, Daniel Gross, Elad Gil and Nate Sauder for encouraging me to put this up, and Nathaniel Horwitz for major editorial help.

 

Appendix: What is a Kaplan-Meier curve?

Those curves you saw up top (illustrating metformin or eating less increasing lifespan) were generated by the following equation. It's ubiquitous in aging biology, and allows you to draw lifespan curves when, for example,  some of the population could be censored.

 

 d_i is the number of events at time i

n_i is the total individuals at risk at time i.

My Ideas - 9.png

References

Table 1: 95 things that make mice live longer

  1. Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … Deursen, J. M. Van. (2016). cells shorten healthy lifespan. Nature, 530(7589), 184–189. http://doi.org/10.1038/nature16932
  2. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., … Miller, R. a. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392–5. doi:10.1038/nature08221
  3. Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., … Auwerx, J. (2016). NAD repletion enhances life span in mice, 6(6292). http://doi.org/10.1126/science.aaf2693
  4. Schriner, S. E., Linford, N. J., Martin, G. M., Treuting, P., Ogburn, C. E., Emond, M., … Rabinovitch, P. S. (2005). Extension of murine life span by overexpression of catalase targeted to mitochondria. Science (New York, N.Y.), 308(5730), 1909–11. doi:10.1126/science.1106653
  5. Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., … Cohen, H. Y. (2012). The sirtuin SIRT6 regulates lifespan in male mice. Nature, 483(7388), 218–21. doi:10.1038/nature10815
  6. Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., … de Cabo, R. (2013). Metformin improves healthspan and lifespan in mice. Nature Communications, 4. doi:10.1038/ncomms3192
  7. Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., … Cai, D. (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497(7448), 211–6. doi:10.1038/nature12143
  8. Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V, Gurnani, P., Mcguinness, O. P., … Kuro-o, M. (2008). Suppression of Aging in Mice by the Hormone Klotho, 309(5742), 1829–1833. http://doi.org/10.1126/science.1112766.Suppression
  9. Selman, C., Tullet, J. M. a, Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., … Withers, D. J. (2009). Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science (New York, N.Y.), 326(5949), 140–4. doi:10.1126/science.1177221
  10. Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Pandolfi, P. P., … Pelicci, P. G. (1999). The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature, 402(6759), 309–13. doi:10.1038/46311
  11. Solon-Biet, S. M., McMahon, A. C., Ballard, J. W. O., Ruohonen, K., Wu, L. E., Cogger, V. C., … Simpson, S. J. (2014). The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metabolism, 19(3), 418–430. http://doi.org/10.1016/j.cmet.2014.02.009
  12. Blüher, M., Kahn, B. B., & Kahn, C. R. (2003). Extended longevity in mice lacking the insulin receptor in adipose tissue. Science (New York, N.Y.), 299(5606), 572–4. doi:10.1126/science.1078223
  13. Latorre-Pellicer, A., Moreno-Loshuertos, R., Lechuga-Vieco, A. V., Sánchez-Cabo, F., Torroja, C., Acín-Pérez, R., … Enríquez, J. A. (2016). Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature, 535(7613), 561–565. http://doi.org/10.1038/nature18618
  14. Brandhorst, S., Choi, I. Y., Wei, M., Cheng, C. W., Sedrakyan, S., Navarrete, G., … Longo, V. D. (2015). A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metabolism, 22(1), 86–99. http://doi.org/10.1016/j.cmet.2015.05.012
  15. Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., … Strong, R. (2014). Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell, 13(3), 468–477. http://doi.org/10.1111/acel.12194
  16. Satoh, A., Brace, C. S., Rensing, N., Cliften, P., Wozniak, D. F., Herzog, E. D., … Imai, S.-I. (2013). Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell metabolism, 18(3), 416–30. doi:10.1016/j.cmet.2013.07.013
  17. Mitchell, S. J., Martin-Montalvo, A., Mercken, E. M., Palacios, H. H., Ward, T. M., Abulwerdi, G., … De Cabo, R. (2014). The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Reports, 6(5), 836–843. http://doi.org/10.1016/j.celrep.2014.01.031
  18. Eisenberg, T., Abdellatif, M., Schroeder, S., Primessnig, U., Stekovic, S., Pendl, T., … Madeo, F. (2016). Cardioprotection and lifespan extension by the natural polyamine spermidine. Nature Medicine, 22(12), 1428–1438. http://doi.org/10.1038/nm.4222
  19. Pyo, J.-O., Yoo, S.-M., Ahn, H.-H., Nah, J., Hong, S.-H., Kam, T.-I., … Jung, Y.-K. (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature communications, 4, 2300. doi:10.1038/ncomms3300
  20. Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. a. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Molecular Medicine, n/a–n/a. doi:10.1002/emmm.201200245
  21. Selman, C., Lingard, S., Choudhury, A. I., Batterham, R. L., Claret, M., Clements, M., … Withers, D. J. (2008). Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 22(3), 807–18. doi:10.1096/fj.07-9261com
  22. Flurkey, K., Papaconstantinou, J., Miller, R. a, & Harrison, D. E. (2001). Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proceedings of the National Academy of Sciences of the United States of America, 98(12), 6736–41. doi:10.1073/pnas.111158898
  23. Brown-Borg, H., Borg, K., Meliska, C., & Bartke, A. (1996). Dwarf mice and the aging process. Nature.
  24. Matheu, A., Maraver, A., Klatt, P., Flores, I., Garcia-Cao, I., Borras, C., … Serrano, M. (2007). Delayed ageing through damage protection by the Arf/p53 pathway. Nature, 448(7151), 375–9. http://doi.org/10.1038/nature05949
  25. Ozanne, S., & Hales, C. (2004). Lifespan: catch-up growth and obesity in male mice. Nature, 427(January).
  26. Miller, R. A., Buehner, G., Chang, Y., Harper, J. M., Sigler, R., & Smith-wheelock, M. (2005). Methionine-deficient diet extends mouse lifespan , slows immune and lens aging , alters glucose , T4 , IGF-I and insulin levels , and increases hepatocyte MIF levels and stress resistance, (February), 119–125. doi:10.1111/j.1474-9726.2005.00152.x
  27. Bitto, A., Ito, T. K., Pineda, V. V., Letexier, N. J., Huang, H. Z., Sutlief, E., … Kaeberlein, M. (2016). Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife, 5(AUGUST), 1–17. http://doi.org/10.7554/eLife.16351
  28. Coschigano, K. T., Clemmons, D., Bellush, L. L., & Kopchick, J. J. (2000). Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology, 141(7), 2608–13.
  29. Wu, J. J., Liu, J., Chen, E. B., Wang, J. J., Cao, L., Narayan, N., … Finkel, T. (2013). Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression. Cell reports, 4(5), 913–20. doi:10.1016/j.celrep.2013.07.030
  30. Ortega-Molina, A., Efeyan, A., Lopez-Guadamillas, E., Muñoz-Martin, M., Gómez-López, G., Cañamero, M., … Serrano, M. (2012). Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell metabolism, 15(3), 382–94. doi:10.1016/j.cmet.2012.02.001
  31. Hofmann, J. W., Zhao, X., De Cecco, M., Peterson, A. L., Pagliaroli, L., Manivannan, J., … Sedivy, J. M. (2015). Reduced expression of MYC increases longevity and enhances healthspan. Cell, 160(3), 477–488. http://doi.org/10.1016/j.cell.2014.12.016
  32. Zhang, Y., Xie, Y., Berglund, E. D., Coate, K. C., He, T. T., Katafuchi, T., … Mangelsdorf, D. J. (2012). The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife, 1, e00065. doi:10.7554/eLife.00065
  33. Baker, D. J., Dawlaty, M. M., Wijshake, T., Jeganathan, K. B., Malureanu, L., van Ree, J. H., … van Deursen, J. M. (2012). Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nature Cell Biology, 15(1), 96–102. http://doi.org/10.1038/ncb2643
  34. Yan, L., Vatner, D. E., O’Connor, J. P., Ivessa, A., Ge, H., Chen, W., … Vatner, S. F. (2007). Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell, 130(2), 247–58. doi:10.1016/j.cell.2007.05.038
  35. Harrison, D. E., Strong, R., Allison, D. B., Ames, B. N., Astle, C. M., Atamna, H., … Miller, R. a. (2013). Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell, (October), n/a–n/a. doi:10.1111/acel.12170
  36. Harrison, D. E., Strong, R., Allison, D. B., Ames, B. N., Astle, C. M., Atamna, H., … Miller, R. a. (2013). Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell, (October), n/a–n/a. doi:10.1111/acel.12170
  37. Riera, E., Huising, M. O., Follett, P., Leblanc, M., Halloran, J., & Andel, R. Van. (2014). TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling, 1023–1036. http://doi.org/10.1016/j.cell.2014.03.051
  38. Mercken, E. M., Mitchell, S. J., Martin-Montalvo, A., Minor, R. K., Almeida, M., Gomes, A. P., … de Cabo, R. (2014). SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell, 13(5), 787–796. http://doi.org/10.1111/acel.12220
  39. Satoh, S., Series, R., Forbush, B., Mcgloin, M., Tyryshkin, a M., Dismukes, G. C., … Walker, L. M. (2006). Transgenic Mice with a Reduced Core Body Temperature Have an Increased Life Span. Nature, 314(November), 825–828. http://doi.org/10.1126/science.1132191
  40. Nóbrega-Pereira, S., Fernandez-Marcos, P. J., Brioche, T., Gomez-Cabrera, M. C., Salvador-Pascual, A., Flores, J. M., … Serrano, M. (2016). G6PD protects from oxidative damage and improves healthspan in mice. Nature Communications, 7, 10894. http://doi.org/10.1038/ncomms10894
  41. Kappeler, L., De Magalhaes Filho, C., Dupont, J., Leneuve, P., Cervera, P., Périn, L., … Holzenberger, M. (2008). Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS biology, 6(10), e254. doi:10.1371/journal.pbio.0060254
  42. Dell’agnello, C., Leo, S., Agostino, A., Szabadkai, G., Tiveron, C., Zulian, A., … Zeviani, M. (2007). Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Human molecular genetics, 16(4), 431–44. doi:10.1093/hmg/ddl477
  43. Sun, L., Sadighi Akha, A. A., Miller, R. A., & Harper, J. M. (2009). Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 64(7), 711–722. http://doi.org/10.1093/gerona/glp051
  44. Liu, X., Jiang, N., Hughes, B., Liu, X., Jiang, N., Hughes, B., … Hekimi, S. (2005). longevity : loss of mclk1 increases cellular fitness and lifespan in mice Evolutionary conservation of the clk-1 -dependent mechanism of longevity : loss of mclk1 increases cellular fitness and lifespan in mice, 2424–2434. doi:10.1101/gad.1352905
  45. Strong, R., Miller, R. a, Astle, C. M., Floyd, R. a, Flurkey, K., Hensley, K. L., … Harrison, D. E. (2008). Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging cell, 7(5), 641–50. doi:10.1111/j.1474-9726.2008.00414.x
  46. Strong, R., Miller, R. a, Astle, C. M., Floyd, R. a, Flurkey, K., Hensley, K. L., … Harrison, D. E. (2008). Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging cell, 7(5), 641–50. doi:10.1111/j.1474-9726.2008.00414.x
  47. Quick, K. L., Ali, S. S., Arch, R., Xiong, C., Wozniak, D., & Dugan, L. L. (2008). A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiology of aging, 29(1), 117–28. doi:10.1016/j.neurobiolaging.2006.09.014
  48. Muzumdar, R., Allison, D. B., Derek, M., Ma, X., Atzmon, G., Francine, H., … Barzilai, N. (2008). Visceral adipose tissue modulates mammalian longevity, 438–440. doi:10.1111/j.1474-9726.2008.00391.x
  49. Cai, W., He, J. C., Zhu, L., Chen, X., Wallenstein, S., Striker, G. E., & Vlassara, H. (2007). Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression. The American journal of pathology, 170(6), 1893–902. doi:10.2353/ajpath.2007.061281
  50. Wang, J., Morita, Y., Han, B., Niemann, S., Löffler, B., & Rudolph, K. L. (2016). Per2 induction limits lymphoid-biased haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing. Nature Cell Biology, 18(5), 480–490. http://doi.org/10.1038/ncb3342
  51. Anisimov, V., Popovich, I. G., Zabezhinski, M. A., Egormin, P. A., Yurova, M. N., Semenchenko, A. V., … Khaitsev, N. V. (2015). Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin http://www.tandfonline.com/doi/pdf/10.4161/15384101.2014.973308. Cell Cycle, 14(1), 46–55. http://doi.org/10.4161/15384101.2014.973308
  52. Sun, L. Y., Spong, a., Swindell, W. R., Fang, Y., Hill, C., Huber, J. a., … Bartke, a. (2013). Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife, 2, e01098–e01098. doi:10.7554/eLife.01098
  53. Hu, D., Cao, P., Thiels, E., Chu, C. T., Wu, G.-Y., Oury, T. D., & Klann, E. (2007). Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase. Neurobiology of learning and memory, 87(3), 372–84. doi:10.1016/j.nlm.2006.10.003
  54. Yang, X., Doser, T. A., Fang, C. X., Nunn, J. M., Janardhanan, R., Zhu, M., … Ren, J. (2006). Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction : role of oxidative stress. FASEB. doi:10.1096/fj.05
  55. Xu, J., Gontier, G., Chaker, Z., Lacube, P., Dupont, J., & Holzenberger, M. (2014). Longevity effect of IGF-1R+/- mutation depends on genetic background-specific receptor activation. Aging Cell, 13(1), 19–28. http://doi.org/10.1111/acel.12145
  56. Matheu, A., Maraver, A., Collado, M., Garcia-Cao, I., Cañamero, M., Borras, C., … Serrano, M. (2009). Anti-aging activity of the Ink4/Arf locus. Aging Cell, 8(2), 152–161. http://doi.org/10.1111/j.1474-9726.2009.00458.x
  57. Junnila, R. K., Duran-Ortiz, S., Suer, O., Sustarsic, E. G., Berryman, D. E., List, E. O., & Kopchick, J. J. (2016). Disruption of the GH receptor gene in adult mice increases maximal lifespan in females. Endocrinology, 157(12), 4502–4513. http://doi.org/10.1210/en.2016-1649
  58. Cargill, S. L., Carey, J. R., Müller, H.-G., & Anderson, G. (2003). Age of ovary determines remaining life expectancy in old ovariectomized mice. Aging cell, 2(3), 185–90.
  59. Gates, A. C., Bernal-Mizrachi, C., Chinault, S. L., Feng, C., Schneider, J. G., Coleman, T., … Semenkovich, C. F. (2007). Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease. Cell metabolism, 6(6), 497–505. doi:10.1016/j.cmet.2007.10.010)
  60. Conover, C. a, Bale, L. K., Mader, J. R., Mason, M. a, Keenan, K. P., & Marler, R. J. (2010). Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A. The journals of gerontology. Series A, Biological sciences and medical sciences, 65(6), 590–9. doi:10.1093/gerona/glq032
  61. López-Domínguez, J. A., Ramsey, J. J., Tran, D., Imai, D. M., Koehne, A., Laing, S. T., … McDonald, R. B. (2015). The Influence of Dietary Fat Source on Life Span in Calorie Restricted Mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 70(10), 1181–1188. http://doi.org/10.1093/gerona/glu177
  62. Enns, L. C., Morton, J. F., Treuting, P. R., Emond, M. J., Wolf, N. S., Dai, D.-F., … Ladiges, W. C. (2009). Disruption of protein kinase A in mice enhances healthy aging. PloS one, 4(6), e5963. doi:10.1371/journal.pone.0005963
  63. Mendias, C. L., Bakhurin, K. I., Gumucio, J. P., Shallal-Ayzin, M. V., Davis, C. S., & Faulkner, J. A. (2015). Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice. Aging Cell, 14(4), 704–706. http://doi.org/10.1111/acel.12339
  64. Nojima, A., Yamashita, M., Yoshida, Y., Shimizu, I., Ichimiya, H., Kamimura, N., … Minamino, T. (2013). Haploinsufficiency of akt1 prolongs the lifespan of mice. PloS one, 8(7), e69178. doi:10.1371/journal.pone.0069178
  65. Du, W. W., Yang, W., Fang, L., Xuan, J., Li, H., Khorshidi, A., … Yang, B. B. (2014). miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7. Cell Death and Disease, 5(7), e1355. http://doi.org/10.1038/cddis.2014.305
  66. Spindler, S. R., Mote, P. L., Lublin, A. L., Flegal, J. M., Dhahbi, J. M., & Li, R. (2015). Nordihydroguaiaretic acid extends the lifespan of drosophila and mice, increases mortality-related tumors and hemorrhagic diathesis, and alters energy homeostasis in mice. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 70(12), 1479–1489. http://doi.org/10.1093/gerona/glu190
  67. Canaan, A., DeFuria, J., Perelman, E., Schultz, V., Seay, M., Tuck, D., … Weissman, S. M. (2014). Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. Proceedings of the National Academy of Sciences, 111(14), 5313–5318. http://doi.org/10.1073/pnas.1323426111
  68. Bobkova, N. V., Evgen’ev, M., Garbuz, D. G., Kulikov, A. M., Morozov, A., Samokhin, A., … Nudler, E. (2015). Exogenous Hsp70 delays senescence and improves cognitive function in aging mice. Proceedings of the National Academy of Sciences, 112(52), 16006–16011. http://doi.org/10.1073/pnas.1516131112
  69. Borrás, C., Monleón, D., Grueso, R. L., Gambini, J., Orlando, L., Pallardó, F. V, … Mora, J. F. De. (2011). RasGrf1 deficiency delays dging i n mice, 3(3), 262–276.
  70. Lopez-Mejia, I. C., De Toledo, M., Chavey, C., Lapasset, L., Cavelier, P., Lopez-Herrera, C., … Tazi, J. (2014). Antagonistic functions of LMNA isoforms in energy expenditure and lifespan. EMBO Reports, 15(5), 529–539. http://doi.org/10.1002/embr.201338126
  71. Wu, C.-Y., Chen, Y.-F., Wang, C.-H., Kao, C.-H., Zhuang, H.-W., Chen, C.-C., … Tsai, T.-F. (2012). A persistent level of Cisd2 extends healthy lifespan and delays aging in mice. Human molecular genetics, 21(18), 3956–68. doi:10.1093/hmg/dds210
  72. Spindler, S. R., Mote, P. L., Li, R., Dhahbi, J. M., Yamakawa, A., Flegal, J. M., … Lublin, A. L. (2013). β 1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice. doi:10.1007/s11357-012-9498-3
  73. Spindler, S. R., Mote, P. L., Li, R., Dhahbi, J. M., Yamakawa, A., Flegal, J. M., … Lublin, A. L. (2013). β 1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice. doi:10.1007/s11357-012-9498-3
  74. Miskin, R., & Masos, T. (1997). Transgenic mice overexpressing urokinase-type plasminogen activator in the brain exhibit reduced food consumption, body weight and size, and increased longevity. The Journal of Gerontology: Biological Science, 52(2), B118–B124. http://doi.org/10.1093/gerona/52A.2.B118
  75. Harper, J. M., Wilkinson, J. E., & Miller, R. a. (2010). Macrophage migration inhibitory factor-knockout mice are long lived and respond to caloric restriction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 24(7), 2436–42. doi:10.1096/fj.09-152223
  76. Singh, S. P., Niemczyk, M., Saini, D., Sadovov, V., Zimniak, L., & Zimniak, P. (2010). Disruption of the mgsta4 gene increases life span of C57BL mice. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 65(1), 14–23. http://doi.org/10.1093/gerona/glp165
  77. List, E. O., Berryman, D. E., Ikeno, Y., Hubbard, G. B., Funk, K., Comisford, R., … Kopchick, J. J. (2015). Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR-/-mice. Aging, 7(7), 500–512.
  78. Doze, V. A., Papay, R. S., Goldenstein, B. L., Gupta, M. K., Collette, K. M., Nelson, B. W., … Perez, D. M. (2011). Long-Term ␣ 1A -Adrenergic Receptor Stimulation Improves Synaptic Plasticity , Cognitive Function , Mood , and Longevity, 80(4), 747–758. doi:10.1124/mol.111.073734.Norepinephrine
  79. Wu, S., Li, Q., Du, M., Li, S.-Y., & Ren, J. (2007). Cardiac-specific overexpression of catalase prolongs lifespan and attenuates ageing-induced cardiomyocyte contractile dysfunction and protein damage. Clinical and experimental pharmacology & physiology, 34(1-2), 81–7. doi:10.1111/j.1440-1681.2007.04540.x
  80. Zhang, S. Q., Cai, W. J., Huang, J. H., Wu, B., Xia, S. J., Chen, X. L., … Shen, Z. Y. (2015). Icariin, a natural flavonol glycoside, extends healthspan in mice. Experimental Gerontology, 69, 226–235. http://doi.org/10.1016/j.exger.2015.06.020
  81. Takeda, T., & Tanabe, H. (2016). Lifespan and reproduction in brain-specific MIR-29-knockdown mouse. Biochemical and Biophysical Research Communications, 471(4), 454–458. http://doi.org/10.1016/j.bbrc.2016.02.055
  82. Kawahara, M., & Kono, T. (2010). Longevity in mice without a father. Human reproduction (Oxford, England), 25(2), 457–61. doi:10.1093/humrep/dep400
  83. Andersen, J. B., Li, X. L., Judge, C. S., Zhou, A., Jha, B. K., Shelby, S., … Hassel, B. A. (2007). Role of 2-5A-dependent RNase-L in senescence and longevity, (October 2006), 3081–3088. doi:10.1038/sj.onc.1210111
  84. De Luca, G., Ventura, I., Sanghez, V., Russo, M. T., Ajmone-Cat, M. A., Cacci, E., … Calamandrei, G. (2013). Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1. Aging cell, 12(4), 695–705. doi:10.1111/acel.12094
  85. Streeper, R. S., Grueter, C. a, Salomonis, N., Cases, S., Levin, M. C., Koliwad, S. K., … Farese, R. V. (2012). Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice. Aging, 4(1), 13–27.
  86. Hoeflich, A., Reyer, A., Ohde, D., Schindler, N., Brenmoehl, J., Spitschak, M., … Wolf, E. (2016). Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD-deficient IGFBP-2 variant in female transgenic mice. Aging Cell, 15(1), 111–117. http://doi.org/10.1111/acel.12413
  87. Conover, C. A., Bale, L. K., & Marler, R. J. (2015). Pregnancy-associated plasma protein-A deficiency improves survival of mice on a high fat diet. Experimental Gerontology, 70, 131–134. http://doi.org/10.1016/j.exger.2015.08.007
  88. Takahashi, K., Noda, Y., Ohsawa, I., Shirasawa, T., & Takahashi, M. (2014). Extended lifespan, reduced body size and leg skeletal muscle mass, and decreased mitochondrial function in clk-1 transgenic mice. Experimental Gerontology, 58, 146–153. http://doi.org/10.1016/j.exger.2014.08.003
  89. Redmann, S. M., & Argyropoulos, G. (2006). AgRP-deficiency could lead to increased lifespan. Biochemical and Biophysical Research Communications, 351(4), 860–864. http://doi.org/10.1016/j.bbrc.2006.10.129
  90. Kovina, M. V, Zuev, V. a, Kagarlitskiy, G. O., & Khodarovich, Y. M. (2013). Effect on lifespan of high yield non-myeloablating transplantation of bone marrow from young to old mice. Frontiers in genetics, 4(August), 144. doi:10.3389/fgene.2013.00144
  91. Shytikov, D., Balva, O., Debonneuil, E., Glukhovskiy, P., & Pishel, I. (2014). Aged mice repeatedly injected with plasma from young mice: a survival study. BioResearch Open Access, 3(5), 226–32. http://doi.org/10.1089/biores.2014.0043
  92. Markovich, D., Ku, M.-C., & Muslim, D. (2011). Increased lifespan in hyposulfatemic NaS1 null mice. Experimental Gerontology.
  93. Vereczki, V., Mansour, J., Pour-Ghaz, I., Bodnar, I., Pinter, O., Zelena, D., … Chinopoulos, C. (2016). Cyclophilin D regulates lifespan and protein expression of aging markers in the brain of mice. Mitochondrion, 34, 115–126. http://doi.org/10.1016/j.mito.2017.03.003
  94. Bale, L. K., West, S. A., & Conover, C. A. (2017). Inducible knockdown of pregnancy-associated plasma protein-A gene expression in adult female mice extends life span. Aging Cell, 1–3. http://doi.org/10.1111/acel.12624
  95. Grieb, B. C., Boyd, K., Mitra, R., & Eischen, C. M. (2016). Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice, 8(10), 590–602.

 

Table 2: 70 things in the clinic that might make people live longer

  1. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021106s031lbl.pdf
  2. https://clinicaltrials.gov/ct2/show/NCT02089334
  3. Chen, T., Hogan, S., Conley, G., Pazmany, C., Wu, Q.-L., McNeil, G. L., … Sexton, D. J. (2007). Discovery and characterization of human antibody inhibitors of pregnancy-associated plasma protein-A. Biological chemistry, 388(5), 507–12. doi:10.1515/BC.2007.058, Mikkelsen, J. H., Gyrup, C., Kristensen, P., Overgaard, M. T., Poulsen, C. B., Laursen, L. S., & Oxvig, C. (2008). Inhibition of the proteolytic activity of pregnancy-associated plasma protein-A by targeting substrate exosite binding. The Journal of biological chemistry, 283(24), 16772–80. doi:10.1074/jbc.M802429200
  4. Vikram, A., & Jena, G. (2010). S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats. Biochemical and biophysical research communications, 398(2), 260–5. doi:10.1016/j.bbrc.2010.06.070, Schäffer, L., Brand, C. L., Hansen, B. F., Ribel, U., Shaw, A. C., Slaaby, R., & Sturis, J. (2008). A novel high-affinity peptide antagonist to the insulin receptor. Biochemical and biophysical research communications, 376(2), 380–3. doi:10.1016/j.bbrc.2008.08.151
  5. https://clinicaltrials.gov/ct2/show/NCT03041701
  6. http://clinicaltrials.gov/ct2/show/NCT00791544
  7. http://clinicaltrials.gov/ct2/results?term=cixutumumab&Search=Search
  8. http://www.astellas.com/en/ir/library/pdf/2q2014_rd_en.pdf (Page 12), http://www.firstwordpharma.com/node/363806#axzz2o4na47BE
  9. http://clinicaltrials.gov/ct2/show/NCT01721577, http://www.axelar.se/docs/Axelar_PR13%20Results%20clinical%20study%20I-II%202011-09-26%20EN.pdf
  10. http://clinicaltrials.gov/ct2/show/NCT00673049, Ma, H., Zhang, T., Shen, H., Cao, H., & Du, J. (2013). The Adverse Events Profile of anti-IGF-1R Monoclonal Antibodies in Cancer Therapy. British journal of clinical pharmacology. doi:10.1111/bcp.12228
  11. http://clinicaltrials.gov/ct2/show/NCT01779336
  12. http://clinicaltrials.gov/ct2/results/displayOpt?flds=a&flds=b&flds=f&flds=n&flds=o&submit_fld_opt=on&term=biib022&show_flds=Y, http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/2612
  13. http://clinicaltrials.gov/ct2/results/displayOpt?flds=a&flds=b&flds=f&flds=n&flds=o&submit_fld_opt=on&term=rg1507&show_flds=Y, Bagatell, R., Herzog, C. E., Trippett, T. M., Grippo, J. F., Cirrincione-Dall, G., Fox, E., … Gore, L. (2011). Pharmacokinetically guided phase 1 trial of the IGF-1 receptor antagonist RG1507 in children with recurrent or refractory solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 17(3), 611–9. doi:10.1158/1078-0432.CCR-10-1731
  14. http://clinicaltrials.gov/ct2/results?term=dalotuzumab&Search=Search, Atzori, F., Tabernero, J., Cervantes, A., Prudkin, L., Andreu, J., Rodríguez-Braun, E., … Baselga, J. (2011). A phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 17(19), 6304–12. doi:10.1158/1078-0432.CCR-10-3336
  15. El-Ami, T., Moll, L., Carvalhal Marques, F., Volovik, Y., Reuveni, H., & Cohen, E. (2013). A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity. Aging cell, 1–10. doi:10.1111/acel.12171
  16. Annunziata, M., Grande, C., Scarlatti, F., Deltetto, F., Delpiano, E., Camanni, M., … Granata, R. (2010). The growth hormone-releasing hormone (GHRH) antagonist JV-1-36 inhibits proliferation and survival of human ectopic endometriotic stromal cells (ESCs) and the T HESC cell line. Fertility and sterility, 94(3), 841–9. doi:10.1016/j.fertnstert.2009.03.093
  17. Siejka, A., Schally, A. V, Block, N. L., & Barabutis, N. (2010). Antagonists of growth hormone-releasing hormone inhibit the proliferation of human benign prostatic hyperplasia cells. The Prostate, 70(10), 1087–93. doi:10.1002/pros.21142
  18. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19667scm044_Sandostatin_lbl.pdf
  19. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf
  20. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019667s058,021008s023lbl.pdf
  21. http://clinicaltrials.gov/ct2/show/NCT00640757
  22. http://clinicaltrials.gov/ct2/show/NCT00427193
  23. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021110s058lbl.pdf
  24. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022088s002s004s005s007s010s012lbl.pdf
  25. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022334s6lbl.pdf
  26. http://www.drugs.com/nda/ridaforolimus_120606.html, http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncologicdrugsadvisorycommittee/ucm296305.pdf
  27. Pearce, L. R., Alton, G. R., Richter, D. T., Kath, J. C., Lingardo, L., Chapman, J., … Alessi, D. R. (2010). Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). The Biochemical journal, 431(2), 245–55. doi:10.1042/BJ20101024
  28. http://clinicaltrials.gov/ct2/show/NCT00937326, Venkatasubramanian, S., Noh, R. M., Daga, S., Langrish, J. P., Joshi, N. V, Mills, N. L., … Newby, D. E. (2013). Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers. Journal of the American Heart Association, 2(3), e000042. doi:10.1161/JAHA.113.000042
  29. http://clinicaltrials.gov/ct2/show/NCT01416376
  30. http://clinicaltrials.gov/ct2/show/NCT00678015
  31. http://www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201-Professional%20Labeling.pdf
  32. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020357s031,021202s016lbl.pdf
  33. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020482s024lbl.pdf
  34. https://clinicaltrials.gov/ct2/show/NCT02531334
  35. Ziegelbauer, K., Gantner, F., Lukacs, N. W., Berlin, A., Fuchikami, K., Niki, T., … Bacon, K. B. (2005). A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity. British journal of pharmacology, 145(2), 178–92. doi:10.1038/sj.bjp.0706176
  36. Leung, C.-H., Chan, D. S.-H., Li, Y.-W., Fong, W.-F., & Ma, D.-L. (2013). Hit identification of IKKβ natural product inhibitor. BMC pharmacology & toxicology, 14(1), 3. doi:10.1186/2050-6511-14-3
  37. https://clinicaltrials.gov/ct2/show/NCT02439216
  38. Miller, S. C., Huang, R., Sakamuru, S., Shukla, S. J., Attene-, M. S., Shinn, P., … Austin, C. P. (2011). Signaling and their Mechanism of Action, 79(9), 1272–1280. doi:10.1016/j.bcp.2009.12.021.Identification
  39. http://clinicaltrials.gov/ct2/show/NCT01869959
  40. https://clinicaltrials.gov/ct2/show/NCT02097277?term=BMS-986036&rank=1
  41. http://clinicaltrials.gov/ct2/show/NCT01442584
  42. http://clinicaltrials.gov/ct2/show/NCT00545805
  43. http://www.vitaminshoppe.com/p/nature-plus-niacinamide-1000-mg-90-tablets/nt-1308#.UrsRAGRDulo
  44. https://chromadex.com/Ingredients/NIAGEN.html
  45. https://clinicaltrials.gov/ct2/show/NCT03176628
  46. http://www.amicusrx.com/preclinical.aspx
  47. https://clinicaltrials.gov/ct2/show/NCT01590888
  48. http://lysosomaltx.com
  49. Braeunig, J. H., Schweda, F., Han, P.-L., & Seifert, R. (2013). Similarly potent inhibition of adenylyl cyclase by P-site inhibitors in hearts from wild type and AC5 knockout mice. PloS one, 8(7), e68009. doi:10.1371/journal.pone.0068009
  50. http://clinicaltrials.gov/ct2/show/NCT01064492
  51. Murray, A. J. (2008). Pharmacological PKA inhibition: all may not be what it seems. Science signaling, 1(22), re4. doi:10.1126/scisignal.122re4
  52. http://clinicaltrials.gov/ct2/show/NCT01363141
  53. http://clinicaltrials.gov/ct2/show/NCT00739687
  54. http://clinicaltrials.gov/ct2/show/NCT00565318
  55. http://www.carolustherapeutics.com
  56. Al-Abed, Y., & VanPatten, S. (2011). MIF as a disease target: ISO-1 as a proof-of-concept therapeutic. Future medicinal chemistry, 3(1), 45–63. doi:10.4155/fmc.10.281
  57. http://www.fda.gov/Drugs/DrugSafety/ucm225444.htm
  58. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021846
  59. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000032634
  60. https://www.nature.com/articles/nbt0104-3
  61. https://clinicaltrials.gov/ct2/show/NCT03268382
  62. https://clinicaltrials.gov/ct2/show/NCT02545283
  63. https://clinicaltrials.gov/ct2/show/NCT00779519
  64. https://clinicaltrials.gov/ct2/show/NCT02974153
  65. https://clinicaltrials.gov/ct2/show/NCT02959190
  66. https://clinicaltrials.gov/ct2/show/NCT02483585
  67. https://clinicaltrials.gov/ct2/show/NCT03303079
  68. https://clinicaltrials.gov/ct2/show/NCT02310763
  69. https://clinicaltrials.gov/ct2/show/NCT03039686
  70. http://www.cypralis.com/aims/research-portfolio

 

Per-section references for longevity explanations

 

Caloric Restriction

  • McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size one figure. The journal of Nutrition, 10(1), 63-79.
  • Solon-Biet, S. M., McMahon, A. C., Ballard, J. W. O., Ruohonen, K., Wu, L. E., Cogger, V. C., … Simpson, S. J. (2014). The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metabolism, 19(3), 418–430. http://doi.org/10.1016/j.cmet.2014.02.009
  • Miller, R. A., Buehner, G., Chang, Y., Harper, J. M., Sigler, R., & Smith-wheelock, M. (2005). Methionine-deficient diet extends mouse lifespan , slows immune and lens aging , alters glucose , T4 , IGF-I and insulin levels , and increases hepatocyte MIF levels and stress resistance, (February), 119–125. doi:10.1111/j.1474-9726.2005.00152.x
  • Newman, J. C., Covarrubias, A. J., Zhao, M., Yu, X., Gut, P., Ng, C. P., ... & Verdin, E. (2017). Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell metabolism, 26(3), 547-557.
  • Liao, C.-Y., Rikke, B. a, Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging cell, 9(1), 92–5. doi:10.1111/j.1474-9726.2009.00533.x
  • Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., ... & Anderson, R. M. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nature communications, 8.
  • Wei, M., Brandhorst, S., Shelehchi, M., Mirzaei, H., Cheng, C. W., Budniak, J., ... & Cohen, P. (2017). Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Science translational medicine, 9(377), eaai8700.

Insulin/IGF

  • Klass, M. (1983). A METHOD FOR THE ISOLATION OF LONGEVITY MUTANTS IN THE NEMATODE CAENORHABDITIS ELEGANS AND INITIAL RESULTS. Mechanisms of ageing and development, 22, 279–286.
  • Friedman, D., & Johnson, T. (1987). A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics, 118(1), 75–86.
  • Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature.
  • Blüher, M., Kahn, B. B., & Kahn, C. R. (2003). Extended longevity in mice lacking the insulin receptor in adipose tissue. Science (New York, N.Y.), 299(5606), 572–4. doi:10.1126/science.1078223
  • List, E. O., Berryman, D. E., Ikeno, Y., Hubbard, G. B., Funk, K., Comisford, R., … Kopchick, J. J. (2015). Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR-/-mice. Aging, 7(7), 500–512.
  • Flurkey, K., Papaconstantinou, J., Miller, R. a, & Harrison, D. E. (2001). Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proceedings of the National Academy of Sciences of the United States of America, 98(12), 6736–41. doi:10.1073/pnas.111158898
  • Brown-Borg, H., Borg, K., Meliska, C., & Bartke, A. (1996). Dwarf mice and the aging process. Nature.
  • Guevara-Aguirre, J., Balasubramanian, P., Guevara-Aguirre, M., Wei, M., Madia, F., Cheng, C. W., ... & de Cabo, R. (2011). Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Science translational medicine, 3(70), 70ra13-70ra13.
  • Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., … de Cabo, R. (2013). Metformin improves healthspan and lifespan in mice. Nature Communications, 4. doi:10.1038/ncomms3192
  • Zhang, Y., Xie, Y., Berglund, E. D., Coate, K. C., He, T. T., Katafuchi, T., … Mangelsdorf, D. J. (2012). The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife, 1, e00065. doi:10.7554/eLife.00065

Parabiosis

  • Ludwig, F. C. and Elashoff, R. M. (1972), MORTALITY IN SYNGENEIC RAT PARABIONTS OF DIFFERENT CHRONOLOGICAL AGE*†. Transactions of the New York Academy of Sciences, 34: 582–587. doi:10.1111/j.2164-0947.1972.tb02712.x
  • Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. a. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433(7027), 760–4. http://doi.org/10.1038/nature03260
  • Ruckh, J. M., Zhao, J. W., Shadrach, J. L., Van Wijngaarden, P., Rao, T. N., Wagers, A. J., & Franklin, R. J. M. (2012). Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell, 10(1), 96–103. http://doi.org/10.1016/j.stem.2011.11.019
  • Villeda, S. a, Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., … Wyss-Coray, T. (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477(7362), 90–4. http://doi.org/10.1038/nature10357
  • Smith, L. K., He, Y., Park, J.-S., Bieri, G., Snethlage, C. E., Lin, K., … Villeda, S. A. (2015). Β2-Microglobulin Is a Systemic Pro-Aging Factor That Impairs Cognitive Function and Neurogenesis. Nature Medicine, 21(8), 932–7. http://doi.org/10.1038/nm.3898
  • Villeda, S. a, Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., … Wyss-Coray, T. (2014). Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine, (May), 1–8. http://doi.org/10.1038/nm.3569
  • Sinha, M., Jang, Y. C., Oh, J., Khong, D., Wu, E. Y., Manohar, R., … Wagers, A. J. (2014). Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science (New York, N.Y.), 344(6184), 649–52. http://doi.org/10.1126/science.1251152
  • Loffredo, F. S., Steinhauser, M. L., Jay, S. M., Gannon, J., Pancoast, J. R., Yalamanchi, P., … Lee, R. T. (2013). Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell, 153(4), 828–839. http://doi.org/10.1016/j.cell.2013.04.015
  • Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., … Wyss-Coray, T. (2017). Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature, 544(7651), 488–492. http://doi.org/10.1038/nature22067

Senescence

  • Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual review of physiology, 75, 685-705.
  • Baker, D. J., Jeganathan, K. B., Cameron, J. D., Thompson, M., Juneja, S., Kopecka, A., ... & Van Deursen, J. M. (2004). BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature genetics, 36(7), 744-749.
  • Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., … van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232–6. doi:10.1038/nature10600
  • Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … Deursen, J. M. Van. (2016). cells shorten healthy lifespan. Nature, 530(7589), 184–189. http://doi.org/10.1038/nature16932

Autophagy

  • Pyo, J.-O., Yoo, S.-M., Ahn, H.-H., Nah, J., Hong, S.-H., Kam, T.-I., … Jung, Y.-K. (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature communications, 4, 2300. doi:10.1038/ncomms3300
  • Sidransky, E., & Lopez, G. (2012). The link between the GBA gene and parkinsonism. The Lancet Neurology, 11(11), 986-998.

Hypothalamus

  • Satoh, S., Series, R., Forbush, B., Mcgloin, M., Tyryshkin, a M., Dismukes, G. C., … Walker, L. M. (2006). Transgenic Mice with a Reduced Core Body Temperature Have an Increased Life Span. Nature, 314(November), 825–828. http://doi.org/10.1126/science.1132191
  • Satoh, A., Brace, C. S., Rensing, N., Cliften, P., Wozniak, D. F., Herzog, E. D., … Imai, S.-I. (2013). Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell metabolism, 18(3), 416–30. doi:10.1016/j.cmet.2013.07.013
  • Kappeler, L., De Magalhaes Filho, C., Dupont, J., Leneuve, P., Cervera, P., Périn, L., … Holzenberger, M. (2008). Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS biology, 6(10), e254. doi:10.1371/journal.pbio.0060254
  • Miskin, R., & Masos, T. (1997). Transgenic mice overexpressing urokinase-type plasminogen activator in the brain exhibit reduced food consumption, body weight and size, and increased longevity. The Journal of Gerontology: Biological Science, 52(2), B118–B124. http://doi.org/10.1093/gerona/52A.2.B118
  • Takeda, T., & Tanabe, H. (2016). Lifespan and reproduction in brain-specific MIR-29-knockdown mouse. Biochemical and Biophysical Research Communications, 471(4), 454–458. http://doi.org/10.1016/j.bbrc.2016.02.055
  • Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., … Cai, D. (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497(7448), 211–6. doi:10.1038/nature12143

Reproductive System

  • Hsin, H., & Kenyon, C. (2009). Signals from the reproductive system regulate the lifespan of C . elegans animal is extended . Our findings suggest that germline signals act, 399(April 1999).
  • Yamawaki, T. M., Arantes-Oliveira, N., Berman, J. R., Zhang, P., & Kenyon, C. (2008). Distinct Activities of the Germline and Somatic Reproductive Tissues in the Regulation of Caenorhabditis elegans9 Longevity. Genetics, 178(1), 513-526.
  • Min, K. J., Lee, C. K., & Park, H. N. (2012). The lifespan of Korean eunuchs. Current Biology, 22(18), R792-R793
  • Cargill, S. L., Carey, J. R., Müller, H.-G., & Anderson, G. (2003). Age of ovary determines remaining life expectancy in old ovariectomized mice. Aging cell, 2(3), 185–90.

Mitochondria

  • Wu, S., Li, Q., Du, M., Li, S.-Y., & Ren, J. (2007). Cardiac-specific overexpression of catalase prolongs lifespan and attenuates ageing-induced cardiomyocyte contractile dysfunction and protein damage. Clinical and experimental pharmacology & physiology, 34(1-2), 81–7. doi:10.1111/j.1440-1681.2007.04540.x
  • Schriner, S. E., Linford, N. J., Martin, G. M., Treuting, P., Ogburn, C. E., Emond, M., … Rabinovitch, P. S. (2005). Extension of murine life span by overexpression of catalase targeted to mitochondria. Science (New York, N.Y.), 308(5730), 1909–11. doi:10.1126/science.1106653
  • Hu, D., Cao, P., Thiels, E., Chu, C. T., Wu, G.-Y., Oury, T. D., & Klann, E. (2007). Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase. Neurobiology of learning and memory, 87(3), 372–84. doi:10.1016/j.nlm.2006.10.003
  • Quick, K. L., Ali, S. S., Arch, R., Xiong, C., Wozniak, D., & Dugan, L. L. (2008). A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiology of aging, 29(1), 117–28. doi:10.1016/j.neurobiolaging.2006.09.014
  • Dell’agnello, C., Leo, S., Agostino, A., Szabadkai, G., Tiveron, C., Zulian, A., … Zeviani, M. (2007). Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Human molecular genetics, 16(4), 431–44. doi:10.1093/hmg/ddl477

Sirtuins

  • Kennedy, B. K., Austriaco, N. R., Zhang, J., & Guarente, L. (1995). Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell, 80(3), 485–96.
  • Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature, 477(7365), E1–E2. doi:10.1038/nature10440
  • Rogina, B., & Helfand, S. L. (2004). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proceedings of the National Academy of Sciences of the United States of America, 101(45), 15998–6003. doi:10.1073/pnas.0404184101
  • Satoh, A., Brace, C. S., Rensing, N., Cliften, P., Wozniak, D. F., Herzog, E. D., … Imai, S.-I. (2013). Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell Metabolism, 18(3), 416–30. doi:10.1016/j.cmet.2013.07.013
  • Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., … Cohen, H. Y. (2012). The sirtuin SIRT6 regulates lifespan in male mice. Nature, 483(7388), 218–21. doi:10.1038/nature10815
  • Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., … Auwerx, J. (2016). NAD repletion enhances life span in mice, 6(6292). http://doi.org/10.1126/science.aaf2693