PERSPECTIVE | BIOLOGICAL SCIENCES |  

Prolonging healthy aging: Longevity vitamins and

proteins
Bruce N. Ames  Authors Info & Affiliations

Edited by Cynthia Kenyon, Calico Labs, San Francisco, CA, and approved September 13, 2018 (received for review May 30, 2018)

October 15, 2018 115 (43) 10836-10844 https://doi.org/10.1073/pnas.1809045115

68,907 | 86    󩤲

Abstract

It is proposed that proteins/enzymes be classified into two classes according to their

essentiality for immediate survival/reproduction and their function in long-term health:

that is, survival proteins versus longevity proteins. As proposed by the triage theory, a
modest deficiency of one of the nutrients/cofactors triggers a built-in rationing
mechanism that favors the proteins needed for immediate survival and reproduction

(survival proteins) while sacrificing those needed to protect against future damage
(longevity proteins). Impairment of the function of longevity proteins results in an

insidious acceleration of the risk of diseases associated with aging. I also propose that
nutrients required for the function of longevity proteins constitute a class of vitamins that

are here named “longevity vitamins.” I suggest that many such nutrients play a dual role
for both survival and longevity. The evidence for classifying taurine as a conditional

vitamin, and the following 10 compounds as putative longevity vitamins, is reviewed: the
fungal antioxidant ergothioneine; the bacterial metabolites pyrroloquinoline quinone

(PQQ) and queuine; and the plant antioxidant carotenoids lutein, zeaxanthin, lycopene, α-
and β-carotene, β-cryptoxanthin, and the marine carotenoid astaxanthin. Because

nutrient deficiencies are highly prevalent in the United States (and elsewhere),
appropriate supplementation and/or an improved diet could reduce much of the

consequent risk of chronic disease and premature aging.

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I propose that an optimal level of many of the known 30 vitamins and essential

minerals/elements (V/M), plus that of 11 new putative vitamins described herein, is necessary
Prolonging healthy aging: Longevity vitamins and proteins     󩤲 
 for promoting healthy aging. The “triage theory” (1) had previously introduced the concept that

proteins/enzymes that are sacrificed on a V/M shortage are necessary for supporting long-term

health. This insight is being broadened here to classify also many V/M as necessary for

supporting long-term health. I present evidence that the deficiency of many V/M specifically
increases the risk of future disease and shortens the lifespan. Thus, I propose that such V/M be

named “longevity vitamins,” and that proteins associated with them be named “longevity

proteins.” Prolongation of healthy aging has not been generally understood as being related to

V/M levels.

Deficiencies in Vitamins and Minerals

Approximately 30 V/M are cofactors necessary for metabolism to function properly and were

discovered because severe dietary deficiencies were linked to serious adverse health effects.
They include vitamins A, B1, B2, B6, B12, biotin, C, choline, D, E, folic acid, K, niacin, pantothenate;

and minerals/elements calcium, chloride, chromium, cobalt, copper, iodine, iron, manganese,

magnesium, molybdenum, phosphorus, potassium, selenium, sodium, sulfur, and zinc. Some

additional important nutrients, the marine omega-3 fatty acids docosahexaenoic acid (DHA)
and eicosapentanoic acid (EPA), are discussed here, although they are not known as vitamins.

Nine essential dietary amino acids are also important for the synthesis of proteins and

hormones (2) but will not be discussed. The abbreviated term V/M is used throughout this

presentation because it refers to a coherent category of nutrients, although only a few

minerals/elements are discussed.

Most of the world’s population—even in developed countries—consume many of the V/M at

levels below those recommended (3, 4). Using as reference the estimated average requirement

(EAR) values [the intake level for a nutrient at which the needs of half of the healthy population

is adequate and half is inadequate (5, 6)], the following numbers are given as examples of the
high percentages of the United States population ingesting V/M quantities below the EAR

(including fortifications and supplements): vitamin D, 70%; vitamin E, 60%; magnesium, 45%;

calcium, 38%; vitamin K, 35%; vitamin A, 34%; vitamin C, 25%; zinc, 8%; vitamin B6, 8%; folate,

8% (7). Intakes of the marine omega-3 fatty acids DHA and EPA are also remarkably low in the
United States population; an EAR has not been set (8). A varied and balanced diet could provide

enough V/M for a healthier and longer life. A diet containing much of its calories as refined

foods and sugar is deficient in V/M and leads to an unhealthy and shorter life.

The association or causality between various diseases of aging and a number of V/M

deficiencies is analyzed here by screening the literature and using as criteria clinical trials,
epidemiology, Mendelian randomization studies, and biochemical and medical literature. A
sampling of the literature covering the link of various diseases with V/M deficiencies is provided

in SI Appendix, SI-1 Vitamin and Mineral Deficiences.

Triage Theory

The triage theory (1) provides a unifying rationale for why modest V/M deficiencies—
Prolonging healthy aging: Longevity vitamins and proteins 
insufficient to elicit overt symptoms of severe deficiency—might contribute significantly to the
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 aging process and the diseases of aging. Briefly, the triage theory posits that a strategic
rationing response has been selected through evolution, which ensures that when a moderate

shortage of a V/M is encountered, the scarce V/M is preferentially retained by those V/M-
dependent proteins/enzymes that are essential for survival and reproduction, such as proteins
essential for early development and immediate survival (i.e., “survival proteins”). At the same

time, proteins/enzymes needed for maintaining long-term health by preventing insidious

damage are starved for that V/M and become increasingly inactive, thus leading to an increase
in diseases of aging. A major aspect of degenerative aging is that the damage is insidious and

clinically not obvious because it accumulates slowly over time and is apparent only later in life.
The connection to V/M shortages is underappreciated.

This concept of triage has been buttressed by our analyses of vitamin K and the element
selenium (9, 10). Vitamin K-dependent proteins could be categorized into those required for
short-term survival (primarily blood-clotting functions) and those involved in long-term health.

A similar triage rationing was found for selenium-dependent proteins (10). Recent human
studies provide additional support for the triage theory with respect to vitamin K and selenium

(SI Appendix, SI-2 Triage Theory). It is noteworthy that in both of these cases about half of the
proteins are affected negatively by a V/M shortage, suggesting that a large price could be paid
in terms of accelerated aging by such a shortage.

The mechanisms by which triage rationing occurs vary: for vitamin K the proteins are found in
physically unconnected tissues. In the case of selenium the rationing is based on the use of two
different transfer RNAs (tRNAs) controlled by a modified base in the tRNA. Thus, different

mechanisms were adopted for the same ultimate outcome in these two examples, suggesting
that they evolved independently.

Although the triage theory (1, 9, 10) was originally thought of as a cofactor-rationing system,
upon further consideration it should be more broadly construed to include a larger variety of
components that are not enzyme cofactors, but are still essential elements in triage rationing.

The trading-off of metabolic resources to achieve a balance between somatic maintenance and
reproductive fitness was proposed in an evolutionary theory of why we age (11). The triage
theory provides a mechanism for achieving such a trade-off.

Rethinking Vitamins: Longevity Proteins and Vitamins

Vitamins and essential minerals are usually thought of as compounds crucial for survival or
protection against severe ill health, as shown by their dramatic short-term effect upon removal
from the diet; most are necessary for critical metabolic functions. The role of vitamins in

healthy aging has been less appreciated. I am introducing two concepts inherent in the triage-
rationing mechanism: longevity proteins and longevity vitamins.

Longevity Proteins and Survival Proteins.

Among the insights derived from the triage theory are the following concepts: (i) not all

proteins/enzymes
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needed for short-term survival; (iii) adequate V/M throughout life plays an important role in

healthy aging. I propose that during triage rationing proteins that are sacrificed to allow for
survival belong to a category with the specific function of protecting against diseases of aging. I

propose to name them longevity proteins. In contrast, those needed for short-term survival
and reproduction, and thus preferentially supplied with a V/M necessary for their function
(besides being also necessary for later health) are referred to as “survival enzymes/proteins.” A

fraction of the cofactor-requiring proteins that are subject to triage rationing are not technically
enzymes (e.g., regulatory or structural proteins).

Longevity Vitamins.

A redefinition of vitamins emerges from the definition of longevity proteins: the concept that

the dietary compounds needed for the function of longevity proteins belong to a special
category—that is, longevity vitamins—the shortage of which result in damage that is
cumulative and insidious. Thus, vitamins may be divided into two general categories: (i)

supporting both survival and longevity proteins (as defined above), and thus subject to triage
rationing; and (ii) supporting health without emphasis on early survival, but with their shortage

leading continuously to accelerated aging, which may or may not be rationed (e.g.,
antioxidants, many of which are not protein cofactors). Some of those that are rationed may
not involve interaction with a protein (e.g., carotenoids).

In addition, I propose that an important consequence of this insight is the likely existence of
compounds that are needed only for longevity, and therefore are not essential for short-term
survival. It is likely that dietary compounds that are not essential for survival and are used

exclusively for protecting and improving healthy longevity would not yet have been recognized
as V/M, because the effects of their deficiency would have been evident only in the form of

insidious late damage. Evidence for 10 putative longevity vitamins is presented below.

Survival V/M That Are also Longevity V/M

Inherent in the triage theory is the concept that most V/M necessary for the proper function of
longevity proteins/enzymes are also survival V/M, having been originally discovered as
cofactors for survival proteins. Thus, these V/M have two effects: on short-term survival and on
long-term health. Besides the examples of vitamin K and selenium as being both essential and

longevity V/M, three additional examples of V/M that have both effects are vitamin D, marine
omega-3 fatty acids (DHA/EPA), and magnesium. The levels of each of these are inadequate in a
large percentage of the American population, and these deficiencies are a major contributor to
unhealthy aging.

Vitamin D.

Vitamin D levels are inadequate in 70% of the United States population. Almost all dark-skinned
people residing in northern latitudes are particularly deficient (12, 13). Vitamin D was long
considered responsible only for protecting against rickets, but it has now been shown to be
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 by UV light to a precursor of vitamin D steroid hormone. Then the final steroid hormone binds
to a protein, the vitamin D receptor protein; the latter interacts with a 12-base regulatory
sequence in vitamin D receptor-dependent genes and regulates them either in a positive or
negative fashion (12, 13). About 2,700 such binding sites have been found in the human
genome as interacting with the vitamin D receptor protein (14). Extensive evidence shows that
vitamin D deficiency causes—or has been associated with—a large number of diseases that

affect healthy aging, such as all-cause mortality, cancer, cardiovascular disease (CVD), diabetes,
brain function, and so forth. Considering this high level of deficiency and the important
implications of vitamin D interactions, it is particularly important to tune up metabolism (15)
with respect to vitamin D. See SI Appendix, SI-3 Survival V/M That Are also Longevity V/M for the
large literature on vitamin D clinical trials and Mendelian randomization studies.

Supplementation with vitamin D, which would prevent and relieve some of these problems, has
been discouraged for two reasons: fear of toxicity (in older studies) and numerous inadequate
clinical trials. Newer evidence on the effect of vitamin D on all-cause mortality supersedes

these toxicity studies, concluding that there was no increased risk even when blood levels of
25(OH)D were as high as 100 ng/mL (16–18).

The use of randomized clinical trials (RCTs) for studying the effect of nutrients, as opposed to
drug trials, can be subject to misinterpretation unless the level of the nutrient is measured both
before supplementation starts and at its end. This precaution is necessary because many of the
subjects may not be deficient in the nutrient being tested and the amount supplemented may
be insufficient to raise levels adequately. The absence of such measurements can lead to
erroneous negative results, as shown for various RCTs for vitamin D (19) and as pointed out

repeatedly in the nutrition literature (20–28). Many conclusions, both in medical journals (e.g.,
refs. 29 and 30) and in books (e.g., ref. 31), that supplemental vitamins are ineffective in
performing some function generally ascribed to them, should be taken skeptically if the RCT did
not include measurements of the vitamin.

Thus, it is clear that vitamin D performs more than just its initially assigned function of
maintaining bone health. It is important for a healthy long life, and thus it is a longevity vitamin.

Marine Omega-3 Fatty Acids, DHA and EPA.

The intake of these compounds is inadequate in most of the United States population (8). Low
EPA and DHA levels in red blood cells were found to be associated with increased all-cause
mortality in a study of 6,501 elderly women followed for 14.9 y (32). A metaanalysis reported
that each 1% increase in plasma DHA/EPA was linked with a 20% decreased risk in all-cause

mortality (33).

DHA/EPA are present in high levels in the central nervous system and are important for brain
and retinal structure and function (34). In an RCT on first-episode schizophrenia patients,

omega-3 fatty acids supplementation prevented cortical loss of gray matter thickness and
promises a possible treatment for schizophrenia (35). The role of DHA in aging, Alzheimer,
Prolonging healthy aging: Longevity vitamins and proteins
Parkinson, schizophrenia, bipolar, and depression have been recently reviewed (34).
    󩤲 
 Low blood levels of DHA/EPA were shown in a 5-y study to be associated with a faster rate of
telomere shortening, a marker of cell aging (36). Supplemental fish oil (2.5 g/d) slowed telomere
shortening and lowered biomarkers of oxidation in older adults (37). Daily supplemental DHA
(2 g/d) increased the rate of clearance of amyloid plaques in people with mild cognitive

impairment (38). DHA/EPA are important for vitamin D steroid hormone effectiveness (13).
Evidence of their role in reducing the risk of heart disease has been obtained (39, 40). Linolenic
acid (omega-3) is now considered an essential fatty acid, but it is still unclear whether it is just
needed as a precursor of DHA/EPA, which are inefficiently made from it.

Magnesium.

Mg is present in the center of the chlorophyll molecule, with plants being a major dietary
source, together with whole grains, nuts, and seeds (41). Mg deficiency affects about 45% of the
United States population and has been associated with increased all-cause mortality, poor DNA
repair capacity, increased risk of lung cancer and various other kinds of cancer, heart disease,

telomere shortening, and risk of stroke (SI Appendix, SI-3 Survival V/M That Are also Longevity
V/M).

A recent review on the subclinical effects of Mg deficiency makes the case that this deficiency is

a principal driver of CVD, a worldwide underrecognized problem, and thus that it is a major
public health crisis (42). Mg is required to convert vitamin D to its active steroid hormone form
(43).

In conclusion, these three examples of V/M deficiencies, together with the vitamin K and
selenium studies, provide considerable evidence that these compounds fit the definition of
longevity V/M, as well as being essential for survival, and that optimizing their intake offers a
way to lengthen healthy longevity.

Conditional Vitamins

A conditional vitamin is synthesized by the body, but not at a level that is sufficient to optimize
metabolism.

Choline.

Choline was the first example of a conditional vitamin (44): only 11% of women achieve the
recommended intake and the average intakes for the population are half to two-thirds of this
recommendation (45); severe choline deficiency results in DNA strand breaks in rodents,
alterations to epigenetic markers and histones, and affects brain development (46–48).

Taurine (2-Aminoethanesulfonic Acid).

Taurine is another example of a conditional vitamin because it is synthesized by animals

(including humans), but not in sufficient amounts. It has been shown to be important in
preventing numerous health problems, such as CVD, brain function, diabetes, and
mitochondrial diseases, as summarized below. Because of taurine’s extensive involvement in
Prolonging healthy aging: Longevity vitamins and proteins     󩤲 
 health problems that lead to long-term damage, it is proposed here that it is also a longevity
vitamin.

The synthesis of taurine involves cysteine decarboxylation and sulfhydryl oxidation. The rate of
its biosynthesis is species-dependent, with a low level in humans, compared with rodents
(which led to the suggestion that supplementation might be beneficial) (49). It is located in the

cytosol and in mitochondria and it is present in virtually all human tissues at millimolar
concentrations; it is especially high in electrically excitable and secretory tissues and in
platelets. A 70-kg human contains about 70 g of taurine (50). An excellent review of all of the
earlier work on taurine is available in Huxtable (50). Most of taurine is acquired from the diet,
mainly from fish and other seafood, seaweed, eggs, and dark-meat poultry (51).

Taurine is particularly important in the mitochondria, where it is present as 5-taurinomethyl-

uridine in tRNA-leu and tRNA-trp, and as 5-taurinomethyl-2-thiouridine in tRNA-glu, tRNA-gln,
and tRNA-lys. In all five tRNAs, it is located in the wobble position, where it functions to read

accurately alternate codons in the mitochondrial genome (52). A taurine modification defect in
mitochondrial tRNA is associated with the mitochondrial diseases MELAS (mitochondrial
encephalopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and MERRF
(myoclonus epilepsy with ragged-red fibers) (52), suggesting causality, and also that a taurine
deficiency could result in the same diseases. Because of the involvement of mitochondria in

energy production, there has been much interest in taurine in sports medicine in humans with
reference to exercise-induced fatigue and recovery, as has been reviewed previously (53). In
addition, a strong case has been made that taurine is the main buffer in mitochondria (54) and
that it moderates mitochondrial oxidant production (55).

Another possibly important function of taurine is its detoxification of chloramine (a very toxic
membrane-soluble oxidant) via its conversion to taurine-chloramine (56, 57).

Examples of several important insidious long-term pathologies that taurine would protect
against are: CVD, brain dysfunction, and diabetes. Taurine effects on CVD have been examined
by numerous RCTs and have been reviewed previously (51). Taurine supplementation lowers
blood pressure, improves vascular function, and raises plasma hydrogen sulfide levels as
shown in a recent RCT with prehypertension patients (58). Taurine consumption was the most

significant factor associated with reduced risk of ischemic heart disease (IHD) in two
international epidemiological studies of CVD in 61 populations (25 countries; n = 14,000):
Japanese people in Okinawa had the highest taurine dietary intake and the lowest incidence of
IHD and longest lifespan. In contrast, Japanese immigrants in Brazil who eat little seafood, but
more meat and salt, had a 17-y shorter lifespan as a consequence of a very high IHD mortality

(59). Other human clinical studies showed that taurine decreases platelet aggregation, serum
cholesterol levels, LDL/triglyceride levels, and enhances cardiac function (60).

Taurine plays an important role in brain development, including neuronal proliferation, stem

cell proliferation, and differentiation; it has no toxic effects in humans (61). It is a

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 chloride channel and it inhibits the N-methyl-d-aspartate receptor. It is also neuroprotective

and has a role in neural development and neurogenesis; it was shown in an RCT that
symptoms of psychopathology were improved by its administration in patients with first-
episode psychosis (62).

Diabetic remediation by taurine has been reviewed previously (63, 64). Its supplementation
remediates diabetic pathologies, including retinopathy, neuropathy, nephropathy, cardiopathy,
atherosclerosis, altered platelet aggregation, and endothelial dysfunction (65). In patients with
type 1 and type 2 diabetes the taurine transporter is up-regulated in mononuclear blood cells,
indicating that increased levels of taurine are sought by the cell (66, 67). In rats, taurine reduces

oxidative stress caused by diabetes (68, 69).

Taurine is important for fetal development, because the human fetus cannot synthesize
taurine, which is provided by the mother via the taurine transporter, and it is necessary for

organ development and protects against development of type 2 diabetes (70). Therefore,
taurine is also a survival vitamin. Transport of taurine (53) is required for normal development

of numerous fetal tissues in several experimental animals. Taurine functions as an osmolyte; it

was shown to be important in that respect in a variety of species, including rodent

investigations that are consistent with the above results on humans (70, 71) (SI Appendix, SI-4

Conditional Vitamins).

Taurine is well established as an important conditional vitamin for survival functions and for
healthy longevity in both humans and experimental animals. I expect that a large class of new

conditional vitamins will be discovered. Possible candidates are lipoic acid, ubiquinone, and
carnitine.

Putative Longevity Vitamins: Ergothionine, Pyrroloquinoline Quinone,

Queuine, Carotenoids

I propose that many of the known vitamins and minerals have, besides a “survival” function,
aging-delaying (“longevity”) functions as well. I also propose that other dietary biochemicals, not

officially recognized as vitamins or as having age-delaying functions, have a positive age-

delaying effect. Several such compounds are discussed as candidates for putative longevity

vitamins: the fungal antioxidant ergothioneine (ESH); the bacterial compounds pyrroloquinoline

quinone (PQQ) and queuine; and seven plant carotenoids. Among these putative longevity
vitamins are specialized dietary antioxidants (ESH, PQQ, and carotenoids) that reduce the

accumulation of long-term oxidative damage (besides other important functions) and are not
normally classified as “survival vitamins.” It should be noted that within this category vitamin C

is categorized as a survival vitamin because, in addition to being an antioxidant, it also

functions as a cofactor for survival proteins. On the other hand, vitamin E is a fat-soluble, free-
radical scavenger/chain-breaking antioxidant, and is not required for any known

protein/enzyme functions. Neither are discussed further. Other important functions, besides
protecting against oxidation, are associated with longevity. The mechanisms by which the body

prevents insidious aging-related damage are likely to be numerous.

Prolonging healthy aging: Longevity vitamins and proteins     󩤲 
 Ergothioneine.

ESH is present in the human diet. It is synthesized by most mushrooms (72), cyanobacteria, and

many types of soil bacteria (73, 74), but not by plants or animals. Various plant foods contain
small amounts of ESH taken up from the soil; animals that eat such plants contain ESH in their

flesh. The edible fungi synthesize ESH to concentrations varying from a very high level (>100
mg/kg wet weight in oyster and king boletus mushrooms) to a much lower level (0.5 mg/kg) in

the white-button commercial mushrooms, which is most commonly eaten. A detailed analysis

suggests that mushrooms are a major ESH source in Europe (75). Foods known to have
moderate levels of ESH (1 mg/kg wet weight) include beef, pork, lamb, and chicken. Oat bran,

black turtle bean, and red kidney bean contain >3 mg/kg (72, 76).

ESH has been shown to be present in almost all human cell and tissue types, often at millimolar
levels in the brain, bone marrow, lens and cornea of the eye, and erythrocytes (77, 78), where it

appears to play a significant role as an antioxidant. Its function as a specialized antioxidant is

thought to be implicated in CVD prevention and its redox chemistry has been reviewed

previously (79, 80). Its levels decrease significantly with age past 80 y, and significantly lower

levels were found in individuals with mild cognitive impairment (81). It has been suggested that
ESH acts as an adaptive antioxidant for the protection of injured tissues (82). Rheumatoid

arthritis has been associated with increased ESH levels in red blood cells in a case-controlled
study (83). It is also present in high concentrations in mitochondria, a major source of oxidants,

and it has been suggested that it may be a vitamin (84).

ESH in mammals is taken up by a specialized transporter, OCTN1 protein (85, 86), which
appears to have been selected for in the European transition from hunter-gatherers to

agriculturalists (87). Lack of this transporter results in oxidative damage to proteins, lipids, and

DNA, and higher levels of mortality in human cells (84). Dysfunctional haplotypes of the ESH
transporter gene are associated with Crohn’s disease (88, 89). The ESH transporter is essential

because deletion of its gene in mice (90) or zebra fish (91) results in oxidative damage to DNA
and lipids. All of these characteristics suggest an involvement in healthy aging. A likely

mechanism of ESH action appears in SI Appendix, SI-5 Putative Longevity Vitamins.

The presence of ESH in human tissues, the essentiality of its transport system, its possible
involvement in CVD prevention, its antioxidant, and cytoprotectant activities, all suggest that

ESH is a putative longevity vitamin.

Pyrroloquinoline Quinone.

PQQ is made by many species of bacteria, but not by animals or plants. It is a cofactor for

several bacterial dehydrogenases, such as glucose and methanol dehydrogenases (92, 93). It is

synthesized by soil bacteria, enters plants from the soil (94), and thus enters human diets; it
was detected in every sample of fruits and vegetables tested at levels 5–10 times higher than in

human tissues and fluids. PQQ is an important plant growth factor imported from rhizobacteria
(95). It is a powerful antioxidant and is much more stable than ascorbic acid; in redox cycling,
Prolonging healthy
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 The health benefits of PQQ in humans have been reviewed recently, including for diabetes,
antioxidant activity, neuroprotection, cognition (96), and lowering the level of C-reactive protein

(i.e., inflammation). In addition, PQQ supplementation improved antioxidant potential and

decreased the levels of mitochondrial-related intermediates and metabolites in urine, providing

support for previous studies that demonstrated that PQQ improved mitochondrial efficiency
(97).

PQQ has been repeatedly suggested to be a vitamin, although arguments have been raised

against it (92). The case for its being classified as a vitamin has become stronger due to a recent

breakthrough study (98) of five mouse proteins that bind PQQ. This work confirmed that the
activity of at least one mammalian enzyme, rabbit lactic dehydrogenase-A, depends on PQQ to

catalyze the key conversion of lactate to pyruvate at physiological PQQ levels (98). This activity
enables mitochondria, when limited in activity by reductive stress (i.e., high NADH/NAD ratio),

to synthesize more ATP as an alternative to exporting lactate. PQQ has also been shown to
induce mitochondrial biogenesis at low physiological levels (∼250 μg/kg in rat) through the

proliferator-activated receptor-γ coactivator-1 α (PGC-1α) in peroxisomes (99, 100).

Experiments in cats and rodents on PQQ are numerous and confirmatory (SI Appendix, SI-5
Putative Longevity Vitamins).

PQQ is promising as a longevity vitamin in humans. It is necessary for mitochondrial health

(although most of the evidence for the latter comes from rodent studies).

Queuine.

Queuine is an evolutionarily ancient compound (101). It is a 7-deazaguanine derivative present

in bacteria, which are unique in their ability to synthesize it and pass it on to plants and animals
(102). Detectable amounts of queuine have been identified in tomatoes, wheat, coconut water,

and milk from humans, cows, and goats (102). Humans and mice recover queuine from either
ingested food or the gut flora. All eukaryotic organisms, including humans, convert queuine to

queuosine by placing it in the wobble position (anticodon) of several tRNAs: aspartic acid,

asparagine, histidine, and tyrosine (101, 103, 104). For details, see SI Appendix, SI-5 Putative
Longevity Vitamins.

Queuine deficiency, uptake, and function have been reviewed (102). It is notable that

eukaryotes have retained a number of dedicated proteins for queuine utilization, which include
a conserved mitochondrial tRNA transglycosylase, thus indicating its essentiality (105). The

cellular uptake of queuine appears to occur through a dedicated transporter (102). Queuine
deficiency in human cells in vitro and in animals results in a reduced level of the cofactor

tetrahydrobiopterin, BH4 (106). BH4 is a necessary cofactor for the conversion of phenylalanine

to tyrosine, of tryptophan to serotonin, of tyrosine to DOPA (which gets converted into

epinephrine and norepinephrine), of arginine to NO, and for the oxidation of alkyl glycerol

lipids (107, 108). The essentiality of BH4 for the hydroxylation of tryptophan to produce
serotonin could be of relevance to numerous neurological conditions, especially considering

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 attention deficit/hyperactivity disorder, bipolar, and schizophrenia (12, 13, 109–111). Queuine-

deficient mice become tyrosine-deficient, dying within 18 d of its withdrawal (112), despite the
fact that tyrosine is a nonessential amino acid, presumably because it results in BH4 deficiency.

A recent key paper (113) shows that queuine and a synthetic analog have been proven effective

in a mouse model of multiple sclerosis in eliciting full remission from the disease. Animals
deficient in the tRNA guanine transglycosylase, and thereby incapable of modifying tRNA, fail to

respond to therapy, implying that modulation of protein translation is the principal means

through which the therapeutic effect is elicited.

The finding that queuine is located in the wobble position of tRNA (an ancient molecule), that a

number of dedicated enzymes for queuine utilization have been strongly conserved in

eukaryotes, the existence of a dedicated transporter, the effect on BH4 synthesis, together with
its broad distribution, all suggest that queuine should be classified as a putative longevity

vitamin. It will be desirable to obtain evidence of human pathologies, and thus of unhealthy
aging, consequent to a lack of queuine.

Carotenoids.

There are ∼600 carotenoids synthesized by plants, but not by animals. They act as antioxidant
pigments in all plants and usually contain 11 conjugated double bonds, which accounts for

their yellow/orange/red colors. All photosynthetic plants synthesize carotenoids to quench

singlet oxygen, a highly energetic and toxic form of oxygen created in cells by strong light. The

toxicity of singlet oxygen is due to its ability to oxidize proteins, lipids, and nucleic acids, which

can lead to cell death (114). The extra singlet oxygen energy is dissipated as heat via the long
chain of conjugated double bonds in these compounds. They mimic enzymes in that one

molecule of carotenoid can destroy hundreds of molecules of singlet oxygen. It should be

noted that because the carotenoid family is very large, carotenoids related to each other may

replace each other to perform the same functions, depending on the individual diet.

The following six carotenoids account for 95% of the carotenoids found in American blood and

brain: lutein, zeaxanthin, lycopene, α- and β-carotene, and β-cryptoxanthin. The importance for
health of a seventh carotenoid, the powerful marine carotenoid astaxanthin, which contains 13

conjugated double bonds, is also discussed (SI Appendix, SI-5 Putative Longevity Vitamins).
These are increasingly being accepted as vitamin-like nutrients (115). There is good evidence

that these carotenoids help optimize a healthy lifespan: low intake of these carotenoids has
been associated with all-cause mortality, macular degeneration and associated blindness,

cognitive decline, CVD, various types of cancer, metabolic syndrome, oxidative damage to DNA,

high blood pressure, hearing loss, decreased visual acuity, inflammation, immune decay, and
cognitive decay. It is well known that α- and β-carotene, and β-cryptoxanthin are precursors of

vitamin A; thus, some of the health effects upon their deficiency may be due to insufficient
vitamin A. A description of their chemical nature and properties, together with a summary of

the analysis of their link to diseases of aging, appears in SI Appendix, SI-5 Putative Longevity

Vitamins. healthy aging: Longevity vitamins and proteins

Prolonging     󩤲 
 Carotenoids are included among putative longevity vitamins because of the evidence that they
protect long-term health. The strength of the evidence varies, but they deserve more attention

for their role for achieving a healthy longevity.

Discussion

Prolonging good health while aging is an important issue in a world with large increases in life
expectancy. Mechanistic, genetic, and epidemiological evidence suggests that the metabolic

trade-off occurring upon a V/M shortage results in an accumulation of insidious damage and

aging-associated diseases. Here I propose that the relatively simple approach of securing
sufficient intake of well-known dietary V/M, plus taurine, plus the 10 putative longevity vitamins

introduced here, could lead to healthy aging by “tuning-up metabolism” (15) and promoting
metabolic harmony and health. Other important nutrients will undoubtedly be found in the

future. Because about one-quarter of enzymes require 1 of the ∼30 survival and longevity V/M

as a cofactor in complex metabolic networks (116), it is clearly important that the organism be
properly supplied with such compounds. By optimizing survival and longevity V/M intake

throughout life, premature, insidious, and increased risk of degenerative diseases may in large
part be preventable.

V/M deficiencies, as indicated by intakes below the EAR, are common in the United States (6, 7,

117) and around the globe, especially among the poor, children, adolescents, the obese, and
the elderly. According to the official National Academy of Medicine measure of inadequacy,

most of the United States population is below the EAR for one or more essential V/M. It should

be noted that the official definition of EAR does not take into consideration that the “healthy”
population sampled may be only “apparently healthy” because evidence is provided herein that

it is actually aging faster due to long-term triage effects. Therefore, official EAR values might
actually have been set too low, because they did not take long-term triage effects into account,

and thus more people would be erroneously considered “adequate.” Thus, a concept derived

from this proposal is that EAR values should be set for longevity V/M by taking into account
long-term effects of longevity V/M.

Evidence is accumulating that lack of foods that are particularly nutrient-rich is a contributor to

diseases of aging. “Healthy foods” are nutrient-dense, containing high levels of V/M, fiber, and
longevity vitamins, relative to calories (5): for example, nuts/seeds, eggs, seafood, vegetables,

and fruits (118–120). These foods are enriched in vitamins to nourish the next generation.
Humans should be able to stay healthier longer during old age if nourished appropriately. It is

important to link a mechanistic understanding of the diseases of aging to the consumption of

individual nutrients and to their synergies (121, 122).

Our emphasis on insidious damage does not imply that V/M deficiency is the only major cause

of the degenerative diseases of aging. For example, many types of cancers, dementias, and

other degenerative diseases may be caused by pathogens (123) or genetics. However, V/M
intervention might also help prevent some of these, as for example, by protecting the immune

system (124),
Prolonging which
healthy defends
aging: againstvitamins
Longevity pathogens inproteins
and elderly individuals.     󩤲 
 Although V/M are generally understood to be important for health, it is not usually understood

that other substances—usually referred to as micronutrients, bioactives, and so forth—are

equally important for health, although not resulting in acute signs upon deficiency. Thus, I
propose to call these compounds, collectively, longevity vitamins, in the interest of clarity and

public health.

Some of the insidious damage due to a nutrient shortage may be reversible once the V/M
intake is increased. However, some insidious damage would not be reversible if it were due to a

mutational event, such as loss of a chromosome (e.g., in the case of vitamin K deficiency, as
mimicked by TGFβI inactivation) or, as in the case of DNA damage, resulting from mutagenic

oxidant release consequent to shortage of the antioxidant selenium.

Obese individuals are paricularly deficient in V/M (125–130), which is a likely explanation,

among others, for a decrease in longevity through an increased frequency of every age-
associated disease that has been examined, including cancer (131), heart disease (132–134),

brain decay (135–137), and immune decay (138). The health and longevity of the obese would
benefit greatly from an improvement in their V/M intake.

It should be noted that plants contain a large number of bioactive chemicals, which are present

in our diets, as for example 8,000 different flavonoids (139). Flavonoids function as “nature’s
pesticides,” the purpose of which is to protect plants from predators (140); many have

beneficial (or toxic) effects in humans at some dose and may function by inducing hormetic

mechanisms (141). There is no evidence, to my knowledge, that these compounds act as

vitamins.

The involvement of tRNA-modified bases in triage rationing in the cases of selenium (10) and of

taurine and queuine provides three examples of such a mechanism of rationing. The use of
tRNA-modified bases suggests that this is an ancient mechanism dating to the RNA world that

presumably preceded the DNA world (142) and may involve many aspects of metabolism.

An important concept relative to the use of vitamins for health is the fact that over 50 human
genetic diseases can be ameliorated by the administration of high doses of supplements (143).

Supplementation raises the concentration of the needed coenzyme to levels that overcome a
defect in the enzyme-binding site (which is likely to be deformed by mutation or aging-related

membrane rigidity) (144), besides possibly affecting the abundance and stability of some

proteins. Some of the mitochondrial decay accompanying aging may be due to membrane
rigidity and be remediable, as shown in rats (145). The remediation of proteins deformed by

mutation or aging provides a simple way to improve health and longevity (144).

The Future

Eventually, the age of preventive medicine will take into consideration the major effects of V/M
components, in addition to genetic factors. The optimization of the nutritional status and of the

level of various biomarkers could be determined by each individual, perhaps through an

analyzer machine
Prolonging healthy using
aging:aLongevity
finger-prick of blood
vitamins (146).
and There is a need for the development of
proteins   
  󩤲
 assays providing a range of the V/M levels required to keep enzymes/proteins optimally

functional. Assays are also needed for the connection of deficiencies of longevity vitamins with
their consequent respective pathologies. Measurements of the activity of longevity proteins are

essential for detection of the functional effects of a low intake of each V/M. Two examples of
consequences of V/M insufficiency, which are measurable, are increased DNA damage and

mitochondrial decay. Understanding the full spectrum of longevity V/M will be augmented in

future years.

The prevention of the degenerative diseases of aging is a different science than curing disease:
it involves expertise in metabolism, nutrition, biochemistry, and genetic regulatory elements

and polymorphisms. This approach is critical for lowering medical costs: it has been estimated
that the European Union would save €4 billion from osteoporosis alone, by using vitamin D and

calcium supplementation (147). The additional benefits derived from an improved V/M

utilization would increase savings.

In conclusion, in addition to keeping physically fit, the low-hanging fruit in prolonging a healthy

aging lies in optimizing V/M intake (e.g., refs. 12, 13, 15, 130, and 148).

Acknowledgments
I thank G. Ferro-Luzzi Ames, J. B. Blumberg, W. B. Grant, E. J. Johnson, V. P. Kelly, J. C. King, R. M. Krauss, J. C.
McCann, R. P. Patrick, M. Profet, R. B. Rucker, J.-P. SanGiovanni, W. C. Willett, and S. H. Zeisel for their
suggestions.

Supporting Information
Appendix (PDF)

DOWNLOAD 279.57 KB

References

1 BN Ames, Low micronutrient intake may accelerate the degenerative diseases of aging through
allocation of scarce micronutrients by triage. Proc Natl Acad Sci USA 103, 17589–17594 (2006).

See all references  | Crossref | PubMed | Google Scholar

2 Y Hou, G Wu, Nutritionally nonessential amino acids: A misnomer in nutritional sciences. Adv Nutr 8,
137–139 (2017).

 Go to reference | Crossref | PubMed | Google Scholar

3 LH Allen, B de Benoist, O Dary, RF Hurrell Guidelines on Food Fortification with Micronutrients (WHO,
Geneva, 2006).

 Go to reference | Google Scholar

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